Other entities represented in this entry:
HGNC Approved Gene Symbol: LMNA
SNOMEDCT: 1003431005, 1010712009, 238870004, 53043001, 715439000, 719451006, 721014007, 725048002, 771272007; ICD10CM: E34.8;
Cytogenetic location: 1q22 Genomic coordinates (GRCh38): 1:156,082,573-156,140,081 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q22 | Cardiomyopathy, dilated, 1A | 115200 | Autosomal dominant | 3 |
| Charcot-Marie-Tooth disease, type 2B1 | 605588 | Autosomal recessive | 3 | |
| Emery-Dreifuss muscular dystrophy 2, autosomal dominant | 181350 | Autosomal dominant | 3 | |
| Emery-Dreifuss muscular dystrophy 3, autosomal recessive | 616516 | Autosomal recessive | 3 | |
| Heart-hand syndrome, Slovenian type | 610140 | Autosomal dominant | 3 | |
| Hutchinson-Gilford progeria | 176670 | Autosomal dominant | 3 | |
| Lipodystrophy, familial partial, type 2 | 151660 | Autosomal dominant | 3 | |
| Malouf syndrome | 212112 | Autosomal dominant | 3 | |
| Mandibuloacral dysplasia | 248370 | Autosomal recessive | 3 | |
| Muscular dystrophy, congenital | 613205 | Autosomal dominant | 3 | |
| Restrictive dermopathy 2 | 619793 | Autosomal dominant | 3 |
The LMNA gene encodes lamin A and lamin C. Lamins are structural protein components of the nuclear lamina, a protein network underlying the inner nuclear membrane that determines nuclear shape and size. The lamins constitute a class of intermediate filaments. Three types of lamins, A, B (see LMNB1; 150340), and C, have been described in mammalian cells (Fisher et al., 1986).
By screening human fibroblast and hepatoma cDNA libraries, Fisher et al. (1986) isolated cDNAs corresponding to lamin A and lamin C. The lamin A and C proteins are predicted to have molecular masses of 74 kD and 65 kD, respectively. Fisher et al. (1986) and McKeon et al. (1986) found that the deduced amino acid sequences from cDNA clones of human lamin A and C are identical for the first 566 amino acids, but that lamin A contains an extra 98 amino acids (corresponding to approximately 9 kD) at the C terminus. Lamin C has 6 unique C-terminal amino acids. Both lamins A and C contain a 360-residue alpha-helical domain with homology to a corresponding alpha-helical rod domain that is the structural hallmark of all intermediate filament proteins. Fisher et al. (1986) and McKeon et al. (1986) concluded that lamin A and lamin C arise by alternative splicing from the same gene.
Guilly et al. (1987) detected a 3-kb lamin A mRNA and a 2.1-kb lamin C mRNA in epithelial HeLa cells, but not in T lymphoblasts. Lamin B was the only lamin present in T lymphoblasts. Guilly et al. (1987) noted that the transport of newly synthesized proteins from the cytoplasm into the nucleus differs from the transport of proteins into other organelles, such as mitochondria, in that sequences are not cleaved and remain a permanent feature of the mature polypeptide. Lamin A appears to be an exception to this rule.
Weber et al. (1989) showed that lamin A is synthesized as a precursor molecule called prelamin A. Maturation of lamin A involves the removal of 18 residues from the C terminus, which is accomplished by isoprenylation and farnesylation involving a C-terminal CAAX (cysteine-aliphatic-aliphatic-any amino acid) box (Sinensky et al., 1994).
By RT-PCR analysis of several human cell lines, Machiels et al. (1996) identified an LMNA splice variant, lamin A-delta-10, that lacks exon 10. The predicted protein lacks 30 amino acids in the lamin A tail, which in full-length lamin A contains an aspartic acid- and glutamine-rich stretch, followed by 4 consecutive histidines. Variable lamin A-delta-10 expression was detected in all cell lines and tissues examined. The ratio of lamin A to lamin A-delta-10 varied among samples. Western blot analysis of a 2-dimensional gel revealed a lamin A doublet with an apparent molecular mass of approximately 70 kD and a second, more basic protein of approximately 65 kD.
Using Western blot analysis, Jung et al. (2012) found that lamins A and C were highly expressed in mouse heart, liver, and kidney, with lamin A showing slightly higher expression than lamin C. In contrast, expression of lamin A was much lower than that of lamin C in cerebral cortex and cerebellum. Immunohistochemical analysis revealed that only vascular and meningeal cells in mouse brain expressed significant lamin A, whereas lamin C showed widespread expression in brain. Northern blot analysis and quantitative RT-PCR confirmed high expression of lamin C, but not lamin A, in mouse cerebral cortex and cerebellum.
Simon et al. (2013) stated that prelamin A is C-terminally farnesylated and carboxymethylated, then proteolytically cleaved after tyr646 (Y646) to generate mature lamin A. Mature lamin A can be further modified by acetylation, phosphorylation, or addition of N-acetylglucosamine, and the rod domain can be sumoylated by SUMO2 (603042). Simon et al. (2013) found that the tail domain of mature lamin A, comprising residues 385 to 646, was modified by SUMO1 (601912).
Lin and Worman (1993) demonstrated that the coding region of the lamin A/C gene spans approximately 24 kb and contains 12 exons. Alternative splicing within exon 10 gives rise to 2 different mRNAs that code for prelamin A and lamin C.
Wydner et al. (1996) mapped the LMNA gene to chromosome 1q21.2-q21.3 by fluorescence in situ hybridization.
Gross (2013) mapped the LMNA gene to chromosome 1q22 based on an alignment of the LMNA sequence (GenBank AY847595) with the genomic sequence (GRCh37).
Lloyd et al. (2002) identified proteins interacting with the C-terminal domain of lamin A by screening a mouse 3T3-L1 adipocyte library in a yeast 2-hybrid interaction screen. Using this approach, the adipocyte differentiation factor SREBP1 (184756) was identified as a novel lamin A interactor. In vitro glutathione S-transferase pull-down and in vivo coimmunoprecipitation studies confirmed an interaction between lamin A and both SREBP1a and 1c. A binding site for lamin A was identified in the N-terminal transcription factor domain of SREBP1, between residues 227 and 487. The binding of lamin A to SREBP1 was noticeably reduced by FPLD mutations. The authors speculated that fat loss seen in laminopathies may be caused in part by reduced binding of the adipocyte differentiation factor SREBP1 to lamin A.
Favreau et al. (2004) analyzed myoblast-to-myotube differentiation in a mouse myogenic cell line overexpressing wildtype or mutant human lamin A. In contrast to clones overexpressing wildtype lamin A, those expressing lamin A with the R453W mutation (150330.0002) differentiated poorly or not at all, did not exit the cell cycle properly, and were extensively committed to apoptosis. Clones expressing the R482W mutation (150330.0011) differentiated normally. Favreau et al. (2004) concluded that lamin A mutated at arginine-453 fails to build a functional scaffold and/or fails to maintain the chromatin compartmentation required for differentiation of myoblasts into myocytes.
Using a novel technique to measure nuclear deformation in response to biaxial strain applied to cells, Lammerding et al. (2004) found that Lmna -/- cells showed increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain compared to wildtype cells. In addition, activity of nuclear factor-kappa-B (NFKB; 164011), a mechanical stress-responsive transcription factor that can act as an antiapoptotic signal, was impaired in the Lmna -/- cells. The findings suggested that lamin A/C deficiency is associated with both defective nuclear mechanics and impaired transcriptional activation.
Broers et al. (2004) used a cell compression device to compare wildtype and Lmna-knockout mouse embryonic fibroblasts, and found that Lmna-null cells showed significantly decreased mechanical stiffness and significantly lower bursting force. Partial rescue of the phenotype by transfection with either lamin A or lamin C prevented gross nuclear disruption, but was unable to fully restore mechanical stiffness. Confocal microscopy revealed that the nuclei of Lmna-null cells exhibited an isotropic deformation upon indentation, despite an anisotropic deformation of the cell as a whole. This nuclear behavior suggested a loss of interaction of the disturbed nucleus with the surrounding cytoskeleton. Actin (102610)-, vimentin (193060)-, and tubulin (191110)-based filaments showed disturbed interaction in Lmna-null cells. Broers et al. (2004) suggested that in addition to the loss of nuclear stiffness, the loss of a physical interaction between nuclear structures (i.e., lamins) and the cytoskeleton may cause more general cellular weakness; they proposed a potential key function for lamins in maintaining cellular tensegrity.
Van Berlo et al. (2005) showed that A-type lamins were essential for the inhibition of fibroblast proliferation by TGF-beta-1 (190180). TGF-beta-1 dephosphorylated RB1 (614041) through protein phosphatase 2A (PPP2CA; 176915), both of which were associated with lamin A/C. In addition, lamin A/C modulated the effect of TGF-beta-1 on collagen production, a marker of mesenchymal differentiation. Van Berlo et al. (2005) proposed a role for lamin A/C in control of gene activity downstream of TGF-beta-1, via nuclear phosphatases such as PPP2CA.
Capanni et al. (2005) showed that the lamin A precursor was specifically accumulated in lipodystrophy cells. Pre-lamin A was located at the nuclear envelope and colocalized with SREBP1. Binding of SREBP1 to the lamin A precursor was detected in patient fibroblasts, as well as in control fibroblasts, forced to accumulate pre-lamin A by farnesylation inhibitors. In contrast, SREBP1 did not interact in vivo with mature lamin A or C in cultured fibroblasts. Inhibition of lamin A precursor processing in 3T3-L1 preadipocytes resulted in sequestration of SREBP1 at the nuclear rim, thus decreasing the pool of active SREBP1 that normally activates PPAR-gamma (601487) and causing impairment of preadipocyte differentiation. This defect could be rescued by treatment with troglitazone, a known PPAR-gamma ligand activating the adipogenic program.
Using yeast 2-hybrid analysis and protein pull-down assays, Libotte et al. (2005) found that the last 4 spectrin repeats at the C terminus of nesprin-2 (SYNE2; 608442), a nuclear membrane scaffold protein, bound directly to a C-terminal region common to both lamins A and C. Knockdown studies with human cell lines revealed that lamin A/C was required for nesprin-2 nuclear envelope localization.
Scaffidi and Misteli (2006) showed that the same molecular mechanism responsible for Hutchinson-Gilford progeria syndrome (HGPS; 176670) is active in healthy cells. Cell nuclei from old individuals acquire defects similar to those of HGPS patient cells, including changes in histone modifications and increased DNA damage. Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging. Scaffidi and Misteli (2006) concluded that their observations implicate lamin A in physiologic aging.
Human immunodeficiency virus (HIV)-1 (see 609423) protease inhibitors (PIs) targeting the viral aspartyl protease are a cornerstone of treatment for HIV infection and disease, but they are associated with lipodystrophy and other side effects. Coffinier et al. (2007) found that treatment of human and mouse fibroblasts with HIV-PIs caused an accumulation of prelamin A. The prelamin A in HIV-PI-treated fibroblasts migrated more rapidly than nonfarnesylated prelamin A, comigrating with the farnesylated form found in ZMPSTE24 (606480)-deficient fibroblasts. HIV-PI-treated heterozygous ZMPSTE24 fibroblasts exhibited an exaggerated accumulation of farnesyl-prelamin A. Western blot and enzymatic analysis showed that HIV-PIs inhibited ZMPSTE24 activity and endoproteolytic processing of a GFP-prelamin A fusion protein, but they did not affect farnesylation of HDJ2 (DNAJA1; 602837) or activity of farnesyltransferase (see 134635), ICMT (605851), and RCE1 (605385) in vitro. Coffinier et al. (2007) concluded that HIV-PIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A, possibly explaining HIV-PI side effects.
Prelamin A is normally prenylated at cys661 (C661), then proteolytically processed by ZMPSTE24 into mature lamin A with a C-terminal Y646 residue. By transfecting HEK293 cells with cDNAs encoding prelamin A with various point mutations, Pan et al. (2007) determined that prenylation at C661 was not necessary for proteolytic processing and targeting of mature lamin A to the nuclear lamina. However, prelamin A that was prenylated but could not be C-terminally processed by ZMPSTE24 mislocalized to the nuclear pore complex. Inhibition of prenylation resulted in correct targeting of mutant prelamin A, suggesting that prenylation itself contributed to mislocalization. Since inhibition of prenylation in cultured cells also inhibits accumulation of progerin at the nuclear pore complex, Pan et al. (2007) proposed that accumulation of prenylated protein at the nuclear pore complex causes nuclear dysmorphology and is cytotoxic.
The nuclear envelope LINC (links the nucleoskeleton and cytoskeleton) complex, which is formed by SUN (e.g., SUN1, 607723) and nesprin (e.g., SYNE1, 608441) proteins, provides a direct connection between the nuclear lamina and the cytoskeleton. Haque et al. (2010) stated that SUN1 and SUN2 interact with LMNA and that LMNA is required for the nuclear envelope localization of SUN2, but not SUN1. They found that LMNA mutations associated with Emery-Dreifuss muscular dystrophy (EDMD2; 181350) and HGPS disrupted interaction of LMNA with mouse Sun1 and human SUN2. Nuclear localization of SUN1 and SUN2 was not impaired in EDMD2 or HGPS cell lines. Expression of SUN1, but not SUN2, at the nuclear envelope was enhanced in some HGPS cells, likely due to increased interaction of SUN1 with accumulated prelamin A. Haque et al. (2010) proposed that different perturbations in LMNA-SUN protein interactions may underlie the opposing effects of EDMD and HGPS mutations on nuclear and cellular mechanics.
Nuclei are precisely positioned in skeletal muscle, with a small number clustered under neuromuscular junctions, and the remainder equally spaced along the periphery of the fiber. By screening 16 different disease-causing lamin A variants, Folker et al. (2011) found that nearly all variants affected microtubule-dependent centrosome orientation, but only those that caused striated muscle disease disturbed actin-dependent nuclear movement and positioning. Wildtype, but not mutant, lamin A anchored SUN- and nesprin-containing LINC complexes that attach nuclei to retrogradely moving actin filaments.
Liu et al. (2011) reported the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS iPSCs showed absence of progerin, and more importantly, lacked the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS iPSCs, progerin and its aging-associated phenotypic consequences were restored. Specifically, directed differentiation of HGPS iPSCs to vascular smooth muscle cells led to the appearance of premature senescence phenotypes associated with vascular aging. Additionally, their studies identified DNA-dependent protein kinase catalytic subunit (PRKDC; 600899) as a downstream target of progerin. The absence of nuclear PRKDC holoenzyme correlated with premature as well as physiologic aging. Because progerin also accumulates during physiologic aging, Liu et al. (2011) argued that their results provided an in vitro iPSC-based model to study the pathogenesis of human premature and physiologic vascular aging.
Chen et al. (2012) showed that cells from Lmna -/- mice, which represent EDMD2, cells from Lmna(L530P/L530P) mice, which represent HGPS, and cells from HGPS patients all had overaccumulation of the inner nuclear envelope SUN1 protein. In wildtype cells, Lmna and Sun1 colocalized at the nuclear envelope. In Lmna -/- cells, larger amounts of Sun1 were found at the nuclear envelope and also in the Golgi. The larger amounts of Sun1 appeared to result from reduced protein turnover. Transfection of increasing amounts of mouse Sun1 into Lmna-null/Sun1-null murine cells resulted in increased prevalence of nuclear herniations and apoptosis, and the herniations appeared to result from Sun1 accumulation in the Golgi. Loss of the Sun1 gene in both mouse models extensively rescued cellular, tissue, organ, and lifespan abnormalities. Similarly, knockdown of overaccumulated SUN1 protein in primary human HGPS cells corrected nuclear defects and cellular senescence. The findings indicated that accumulation of SUN1 is a common pathogenetic event in these disorders.
Jung et al. (2012) found that mouse prelamins A and C both contain at least 1 binding site for microRNA-9 (MIR9; 611186) in their 3-prime UTRs. Mir9 downregulated lamin A expression by reducing prelamin A mRNA, but it did not downregulate lamin C expression. The findings suggested that high expression of Mir9 causes the low amount of lamin A, relative to lamin C, in mouse brain.
Using knockin mice expressing prelamin A with alterations in its 3-prime UTR, Jung et al. (2014) showed that Mir9 repressed lamin A expression in cerebral cortex and cerebellum. Mutation of the Mir9-binding site in the 3-prime UTR of prelamin A or replacement of the 3-prime UTR of prelamin A with that of prelamin C resulted in enhanced lamin A expression in brain. Jung et al. (2014) proposed that reduced expression of prelamin A in brain might explain why children with HGPS are spared neurodegenerative disease.
In mice, Ho et al. (2013) found that lamin A/C-deficient (Lmna-null) and Lmna(N195K/N195K) (see 150330.0007) mutant cells have impaired nuclear translocation and downstream signaling of the mechanosensitive transcription factor megakaryoblastic leukemia-1 (MKL1; 606078), a myocardin family member that is pivotal in cardiac development and function. Altered nucleocytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna-null and Lmna(N195K/N195K) mutant cells. Ectopic expression of the nuclear envelope protein emerin (300384), which is mislocalized in Lmna mutant cells and also linked to Emery-Dreifuss muscular dystrophy (310300) and dilated cardiomyopathy, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. Ho et al. (2013) concluded that their findings presented a novel mechanism that could provide insight into the disease etiology for the cardiac phenotype in many laminopathies, whereby lamin A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.
Simon et al. (2013) hypothesized that extensive posttranslational modification of mature lamin A may regulate its interactions with its binding partners, including actin, titin (TTN; 188840), emerin, and SREBP1. They found that lys420 (K420) and K486 in lamin A were modified by SUMO1. K420 lies within the nuclear localization signal, and K486 lies within the immunoglobulin (Ig)-fold. Simon et al. (2013) proposed that SUMO modification of K420 might inhibit lamin A/C binding to cyclin D3 (CCND3; 123834) or core histones that require an unmodified nuclear localization signal, or that it might inhibit binding of lamin A/C to alpha-importin (see 600686). They suggested that SUMO1 modification of K486 might block partners that require an unmodified Ig-fold.
Using in situ proximity ligation assays, reporter gene assays, and biochemical analysis, Vadrot et al. (2015) found that the interaction of SREBP1 with lamin A and lamin C occurs at the nuclear periphery and in the nucleoplasm. Interactions involved the Ig fold common to preLMNA, LMNA, and LMNC, and were stronger when SREBP1 was bound to sterol response elements (SREs) in DNA. SREBP1, LMNA, and SREs formed ternary complexes in vitro. The interaction was inhibitory, and overexpression of A-type lamins reduced transcriptional activity of SREBP1.
Reviews
Schreiber and Kennedy (2013) reviewed the disorders caused by mutations in nuclear lamins and other proteins of the nuclear envelope as well as the mechanisms underlying disease pathology.
Mutations in the LMNA gene cause a wide range of human diseases. Since more than 10 different clinical syndromes have been attributed to LMNA mutations, many of which show overlapping features, attempts at broad classification have been proposed. Worman and Bonne (2007) suggested that the disorders may be classified into 4 major types: diseases of striated and cardiac muscle; lipodystrophy syndromes; peripheral neuropathy; and premature aging. Benedetti et al. (2007) suggested 2 main groups: (1) neuromuscular and cardiac disorders, and (2) lipodystrophy and premature aging disorders. The phenotypic heterogeneity of diseases resulting from a mutation in a single gene can be explained by the numerous roles of the nuclear lamina, including maintenance of nuclear shape and structure, as well as functional roles in transcriptional regulation and heterochromatin organization (review by Capell and Collins, 2006).
Genschel and Schmidt (2000) compiled a list of 41 known mutations, predominantly missense, in the LMNA gene. Twenty-three different mutations had been shown to cause autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350). Three mutations had been reported to cause what was formerly designated autosomal dominant limb-girdle muscular dystrophy (LGMD1B), reclassified as EDMD2 by Straub et al. (2018). Eight mutations were known to result in dilated cardiomyopathy (CMD1A; 115200), and 7 mutations were reported to cause familial partial lipodystrophy (FPLD2; 151660). In addition, 1 mutation in LMNA (H222Y; 150330.0014) appeared to be responsible for an autosomal recessive, atypical form of Emery-Dreifuss muscular dystrophy (EDMD3; 616516).
Muscular Dystrophies
In 5 families with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), Bonne et al. (1999) identified 4 mutations in the LMNA gene (150330.0001-150330.0004) that cosegregated with the disease phenotype. These findings represented the first identification of mutations in a component of the nuclear lamina as a cause of an inherited muscle disorder. The authors noted that lamins interact with integral proteins of the inner nuclear membrane, including emerin (300384), which is mutated in the X-linked form of Emery-Dreifuss muscular dystrophy (EDMD1; 310300).
Raffaele di Barletta et al. (2000) showed that heterozygous mutations in LMNA may cause diverse phenotypes ranging from typical EDMD to no phenotypic effect. LMNA mutations in patients with autosomal dominant EDMD occur in the tail and in the 2A rod domain of the protein, suggesting that unique interactions between lamin A/C and other nuclear components have an important role in cardiac and skeletal muscle function. They identified a homozygous LMNA mutation (H222Y; 150330.0014) in 1 patient born of consanguineous unaffected parents, consistent with autosomal recessive inheritance (EDMD3) and a severe atypical phenotype lacking cardiac features.
Muchir et al. (2000) found mutations in the LMNA gene in 3 families with LGMD1B, reclassified as EDMD2 by Straub et al. (2018): a missense mutation (150330.0017), a deletion of a codon (150330.0018), and a splice donor site mutation (150330.0019). The 3 mutations were identified in all affected members of the corresponding families and were absent in 100 unrelated control subjects.
Quijano-Roy et al. (2008) described a form of congenital muscular dystrophy (MDC) with onset in the first year of life in 15 children resulting from de novo heterozygous mutations in the LMNA gene (see, e.g., 150330.0047-150330.0049). Three patients had severe early-onset disease, with decreased fetal movements in utero, no motor development, severe hypotonia, diffuse limb and axial muscle weakness and atrophy, and talipes foot deformities. The remaining 12 children initially acquired head and trunk control and independent ambulation, but most lost head control due to neck extensor weakness, a phenotype consistent with 'dropped head syndrome.' Ten children required ventilatory support. Cardiac arrhythmias were observed in 4 of the oldest patients, but were symptomatic only in 1. Quijano-Roy et al. (2008) concluded that the identified LMNA mutations appeared to correlate with a relatively severe phenotype, broadening the spectrum of laminopathies. The authors suggested that this group of patients may define a new disease entity, which they designated LMNA-related congenital muscular dystrophy (613205).
Benedetti et al. (2007) reported 27 individuals with mutations in the LMNA gene resulting in a wide range of neuromuscular disorders. Phenotypic analysis yielded 2 broad groups of patients. One group included patients with childhood onset who had skeletal muscle involvement with predominant scapuloperoneal and facial weakness, consistent with EDMD or congenital muscular dystrophy. The second group included patients with later or adult onset who had cardiac disorders or a limb-girdle myopathy, consistent with LGMD1B. Those in the group with early onset tended to have missense mutations, whereas those in the group with adult onset tended to have truncating mutations. Analysis of the variants showed that those associated with early-onset phenotypes were primarily found in the Ig-like domain and in coil 2A, which may interfere with binding to specific ligands. Those associated with later onset were mostly located in the rod domain and in coil 2B, which was predicted to affect the surface of lamin A/C dimers and lead to impaired filament assembly. Benedetti et al. (2007) speculated that there may be 2 different pathogenetic mechanisms associated with neuromuscular LMNA-related disorders: late-onset phenotypes may arise through loss of LMNA function secondary to haploinsufficiency, whereas dominant-negative or toxic gain-of-function mechanisms may underlie the more severe early phenotypes.
Scharner et al. (2011) identified LMNA mutations in 61 (23.9%) of 255 patients with muscular dystrophy. Eleven of the patients had previously been reported by Brown et al. (2001). Among the remaining 50 patients from the United States and Canada, Scharner et al. (2011) found 37 mutations, including 15 novel ones. The mutations were scattered throughout the gene. In vitro functional expression studies performed on some of the mutations (e.g., R249W; 150330.0048) showed that they resulted in increased expression of mutant LMNA, mislocalization of the protein in the nucleus, abnormal nuclear morphology with lobules, and mislocalization of lamin B (LMNB; 150340).
In 4 sibs, born of consanguineous Spanish parents, with EDMD3, Jimenez-Escrig et al. (2012) identified a homozygous missense mutation in the LMNA gene (R225Q; 150330.0054). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in 200 control chromosomes. Functional studies of the variant were not performed. Two heterozygous carriers had no muscular symptoms, but developed cardiac arrhythmias late in life.
In 2 sibs from a family of Hutterite descent with EDMD3 and features of partial lipodystrophy, Wiltshire et al. (2013) identified a homozygous missense mutation in the LMNA gene (R482Q; 150330.0010).
Dilated Cardiomyopathy and Cardiac Conduction Defects
Fatkin et al. (1999) studied the LMNA gene in 11 families with autosomal dominant dilated cardiomyopathy and conduction system disease (CMD1A; 115200) linked to a region on chromosome 1 overlapping that of the LMNA gene. They identified 5 novel missense mutations (150330.0004-150330.0009): 4 in the alpha-helical rod domain of lamin A, and 1 in the tail domain of lamin C. No family members with mutations had joint contractures or skeletal myopathy characteristic of autosomal dominant Emery-Dreifuss muscular dystrophy. Furthermore, serum creatine kinase levels were normal in family members with mutations of the lamin A rod domain, but mildly elevated in some family members with a defect in the lamin C tail domain. The authors noted that mutations in the rod domain of the protein led to dilated cardiomyopathy, whereas mutations in the head or tail domain caused Emery-Dreifuss muscular dystrophy.
Van der Kooi et al. (2002) reported a sporadic patient and 2 unrelated families with mutations in the LMNA gene who presented with varying degrees and combinations of muscular dystrophy, partial lipodystrophy, and cardiomyopathy with conduction defects, presumably due to single mutations (see 150330.0003 and 150330.0005).
Sebillon et al. (2003) screened the coding sequence of LMNA in DNA samples from 66 index cases of dilated cardiomyopathy with or without associated features. They identified a glu161-to-lys mutation (E161K; 150330.0028) in a family with early-onset atrial fibrillation preceding or coexisting with dilated cardiomyopathy, the previously described R377H mutation (150330.0017) in the family with quadriceps myopathy associated with dilated cardiomyopathy previously reported by Charniot et al. (2003), and a 28insA mutation (150330.0029) leading to a premature stop codon in a third family with dilated cardiomyopathy with conduction defects. No mutation in LMNA was found in cases with isolated dilated cardiomyopathy.
Meune et al. (2006) investigated the efficacy of implantable cardioverter-defibrillators (ICDs) in the primary prevention of sudden death in patients with cardiomyopathy due to lamin A/C gene mutations. Patients referred for permanent cardiac pacing were systematically offered the implantation of an ICD. The patients were enrolled solely on the basis of the presence of lamin A/C mutations associated with cardiac conduction defects. Indications for pacemaker implantation were progressive conduction block and sinus block. In all, 19 patients were treated. Meune et al. (2006) concluded that ICD implantation in patients with lamin A/C mutations who are in need of a pacemaker is effective in treating possibly lethal tachyarrhythmias, and that implantation of an ICD, rather than a pacemaker, should be considered for such patients.
Taylor et al. (2003) screened the LMNA gene in 40 families and 9 sporadic patients with CMD with or without muscular dystrophy and identified mutations in 3 families (see, e.g., 150330.0017) and 1 sporadic patient (S573L; 150330.0041). All mutations involved a conserved residue, cosegregated with the disease within the families, and were not found in 300 control chromosomes. LMNA mutation carriers had a severe and progressive form of CMD with significantly poorer cumulative survival compared to noncarrier CMD patients.
Dilated Cardiomyopathy and Hypergonadotropic Hypogonadism
In a 17-year-old Caucasian female with premature ovarian failure and dilated cardiomyopathy, who had features consistent with atypical Werner syndrome (see 277700) but who was negative for mutation in the RECQL2 gene (604611), Nguyen et al. (2007) identified heterozygosity for a missense mutation in the LMNA gene (L59R; 150330.0052). The authors suggested the diagnosis of a laminopathy, most likely an atypical form of mandibuloacral dysplasia (see 248370).
In a 15-year-old Caucasian girl with premature ovarian failure and dilated cardiomyopathy, McPherson et al. (2009) identified heterozygosity for the L59R mutation in the LMNA gene. McPherson et al. (2009) noted phenotypic similarities between this patient and the patient previously reported by Nguyen et al. (2007), who carried the same mutation, as well as a patient originally described by Chen et al. (2003) with an adjacent A57P mutation in LMNA (150330.0030). Features common to these 3 patients included premature ovarian failure, dilated cardiomyopathy, lipodystrophy, and progressive facial and skeletal changes involving micrognathia and sloping shoulders, but not acroosteolysis. Although the appearance of these patients was somewhat progeroid, none had severe growth failure, alopecia, or rapidly progressive atherosclerosis, and McPherson et al. (2009) suggested that the phenotype represents a distinct laminopathy involving dilated cardiomyopathy and hypergonadotropic hypogonadism (212112).
Lipodystrophy Disorders
Patients with Dunnigan-type familial partial lipodystrophy, or partial lipodystrophy type 2 (FPLD2; 151660), are born with normal fat distribution, but after puberty experience regional and progressive adipocyte degeneration, often associated with profound insulin resistance and diabetes. Cao and Hegele (2000) hypothesized that the analogy between the regional muscle wasting in autosomal dominant Emery-Dreifuss muscular dystrophy and the regional adipocyte degeneration in FPLD, in addition to the chromosomal localization of the FPLD2 locus on 1q21-q22, made LMNA a good candidate gene for FPLD2. Studies of 5 Canadian probands with familial partial lipodystrophy of Dunnigan type indicated that each had a novel missense mutation (R482Q; 150330.0010) that cosegregated with the lipodystrophy phenotype and was absent from 2,000 normal alleles.
Shackleton et al. (2000) identified 5 different missense mutations in the LMNA gene (see, e.g., 150330.0010-150330.0012) among 10 kindreds and 3 individuals with partial lipodystrophy. All of the mutations occurred in exon 8, which the authors noted is within the C-terminal globular domain of lamin A/C. Flier (2000) commented on the significance of LMNA mutations in partial lipodystrophy.
Vantyghem et al. (2004) characterized the neuromuscular and cardiac phenotypes of FPLD patients bearing the heterozygous R482W mutation. Fourteen patients from 2 unrelated families, including 10 affected subjects, were studied. Clinical and histologic examination showed an incapacitating, progressive limb-girdle muscular dystrophy in a 42-year-old woman that had been present since childhood, associated with a typical postpubertal FPLD phenotype. Six of 8 adults presented the association of calf hypertrophy, perihumeral muscular atrophy, and a rolling gait due to proximal lower limb weakness. Muscular histology was compatible with muscular dystrophy in one of them and/or showed a nonspecific excess of lipid droplets (in 3 cases). Cardiac septal hypertrophy and atherosclerosis were frequent in FPLD patients. In addition, a 24-year-old FPLD patient had a symptomatic second-degree atrioventricular block. Vantyghem et al. (2004) concluded that most lipodystrophic patients affected by the FPLD-linked R482W mutation show muscular and cardiac abnormalities.
Mandibuloacral dysplasia (see 248370) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. Patients with MAD frequently have partial lipodystrophy and insulin resistance, which are features seen in FPLD. In all affected members of 5 consanguineous Italian families with MAD, Novelli et al. (2002) identified a homozygous missense mutation (R527H; 150330.0021) in the LMNA gene. Patient skin fibroblasts showed nuclei that presented abnormal lamin A/C distribution and a dysmorphic envelope, demonstrating the pathogenic effect of the mutation.
In affected members of a consanguineous family from north India, Plasilova et al. (2004) identified a homozygous missense mutation in the LMNA gene (150330.0033). The extent of skeletal lesions in this family were consistent with MAD, but affected individuals also had classic features of progeria. Plasilova et al. (2004) suggested that autosomal recessive HGPS and mandibuloacral dysplasia may represent a single disorder with varying degrees of disease severity.
Decaudain et al. (2007) identified changes in codon 482 of the LMNA gene (see, e.g., R482Q, 150330.0010 and R482W, 150330.0011) in 17 of 277 unrelated adults investigated for lipodystrophy and/or insulin resistance. All 17 had classic features of FPLD2. Ten additional patients who fulfilled the International Diabetes Federation diagnostic criteria for metabolic syndrome were found to have heterozygous LMNA mutations that were not in codon 482, but affected all 3 domains of the protein, the N terminal, central rod domain, and C terminal globulin domain (see, e.g., R399C; 150330.0043). Because the phenotype of these patients was not typical of FPLD2, the diagnosis of laminopathy was delayed. Although lipodystrophy was less severe than in typical FPLD2, common features included calf hypertrophy, myalgia, and muscle cramps or weakness. Two patients had cardiac conduction disturbances. Metabolic alterations were prominent, especially insulin resistance and hypertriglyceridemia.
Charcot-Marie-Tooth Disease Type 2B1
In affected members of inbred Algerian families with an axonal form of Charcot-Marie-Tooth disease linked to chromosome 1q21.2-q21.3 (CMT2B1; 605588), De Sandre-Giovannoli et al. (2002) found a shared common homozygous ancestral haplotype that was suggestive of a founder mutation and identified a unique mutation in the LMNA rod domain (R298C; 150330.0020). Ultrastructural studies of sciatic nerves of Lmna-null mice showed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies.
Hutchinson-Gilford Progeria Syndrome and Other Premature Aging Syndromes
Eriksson et al. (2003) identified de novo heterozygous point mutations in lamin A that cause Hutchinson-Gilford progeria syndrome (HGPS; 176670). Eighteen of 20 classic cases of HGPS harbored the identical de novo single-base substitution resulting in a silent gly-to-gly change at codon 608 within exon 11 (150330.0022). This change creates an exonic consensus splice site and activates cryptic splicing, leading to deletion of 50 codons at the end of prelamin A. This prelamin A still retains the CAAX box but lacks the site for endoproteolytic cleavage. Eriksson et al. (2003) suggested that there is at least 1 site for phosphorylation, ser625, that is deleted in the abnormal lamin A protein. De Sandre-Giovannoli et al. (2003) independently identified the heterozygous exon 11 cryptic splice site activation mutation (1824C-T+1819-1968del; 150330.0022) in 2 HGPS patients. Later cellular studies (Capell et al., 2005; Glynn and Glover, 2005; Toth et al., 2005) indicated that Hutchinson-Gilford progeria syndrome results from the production of a truncated prelamin A, called progerin, which is farnesylated at its C terminus and accumulates at the nuclear envelope, causing misshapen nuclei (Yang et al., 2006).
Werner syndrome (277700) is an autosomal recessive progeroid syndrome caused by mutation in the RECQL2 gene (WRN; 604611). Chen et al. (2003) reported that of 129 index patients referred to their international registry for molecular diagnosis of Werner syndrome, 26 (20%) had wildtype RECQL2 coding regions and were categorized as having 'atypical Werner syndrome' or 'non-WRN' on the basis of molecular criteria. Because of some phenotypic similarities between Werner syndrome and laminopathies including Hutchinson-Gilford progeria, Chen et al. (2003) sequenced all exons of the LMNA gene in these 26 individuals and found heterozygosity for novel missense mutations in LMNA in 4 (15%): A57P (150330.0030), R133L (150330.0027) in 2 persons, and L140R (150330.0031). Hegele (2003) stated that the clinical designation of Werner syndrome for each of the 4 patients of Chen et al. (2003), in whom mutations in the LMNA gene were found, appeared somewhat insecure. He noted that the comparatively young ages of onset in the patients with mutant LMNA would be just as consistent with late-onset Hutchinson-Gilford syndrome as with early-onset Werner syndrome. Patients with so-called atypical Werner syndrome and mutant LMNA also expressed components of nonprogeroid laminopathies. Hegele (2003) suggested that genomic DNA analysis can help draw a diagnostic line that clarifies potential overlap between older patients with Hutchinson-Gilford syndrome and younger patients with Werner syndrome, and that therapies may depend on precise molecular classification.
McPherson et al. (2009) suggested that the patient in whom Chen et al. (2003) identified an A57P LMNA mutation had a distinct phenotype involving dilated cardiomyopathy and hypergonadotropic hypogonadism (212112).
Csoka et al. (2004) screened 13 cell lines from atypical progeroid patients for mutation in the LMNA gene. They identified 3 novel heterozygous missense mutations in the LMNA gene in 3 patients: a 13-year-old female with a progeroid syndrome, a 15-year-old male with a lipodystrophy, and a 20-year-old male with 'atypical progeria.' The mutations identified in the last 2 patients were the most 5-prime and 3-prime missense mutations, respectively, that had been identified in LMNA.
Reddel and Weiss (2004) reported that transcription efficiencies of the mutant and wildtype LMNA alleles were equivalent in HGPS. The mutant allele gave 2 types of transcripts that encoded truncated and normal lamin A. Abnormally spliced progerin transcript constituted the majority (84.5%) of the total steady-state mRNA derived from the mutant allele. The abnormally spliced progerin transcript was a minority (40%) of all lamin A transcripts obtained from both alleles. Reddel and Weiss (2004) concluded that the mutated progerin functions as a dominant negative by interfering with the structure of the nuclear lamina, intranuclear architecture, and macromolecular interactions, which collectively would have a major impact on nuclear function.
Fibroblasts from individuals with HGPS have severe morphologic abnormalities in nuclear envelope structure. Scaffidi and Misteli (2005) showed that the cellular disease phenotype is reversible in cells from individuals with HGPS. Introduction of wildtype lamin A protein did not rescue the cellular disease manifestations. The mutant LMNA mRNA and lamin A protein could be efficiently eliminated by correction of the aberrant splicing event using a modified oligonucleotide targeted to the activated cryptic splice site. Upon splicing correction, HGPS fibroblasts assumed normal nuclear morphology, the aberrant nuclear distribution and cellular levels of lamina-associated proteins were rescued, defects in heterochromatin-specific histone modifications were corrected, and proper expression of several misregulated genes was reestablished. The results established proof of principle for the correction of the premature aging phenotype in individuals with HGPS.
Huang et al. (2005) designed short hairpin RNAs (shRNA) targeting mutated pre-spliced or mature LMNA mRNAs and expressed them in HGPS fibroblasts carrying the 1824C-T mutation (150330.0022). One of the shRNAs reduced the expression levels of mutant lamin A (so-called LA delta-50) to 26% or lower. The reduced expression was associated with amelioration of abnormal nuclear morphology, improvement of proliferative potential, and reduction in the numbers of senescent cells.
Moulson et al. (2007) reported 2 unrelated patients with extremely severe forms of HGPS associated with unusual mutations in the LMNA gene (150330.0036 and 150330.0040, respectively). Both mutations resulted in increased use of the cryptic exon 11 donor splice site that is also observed with the common 1824C-T mutation (150330.0022). As a consequence, the ratios of mutant progerin mRNA and protein to wildtype were higher than in typical HGPS patients. The findings indicated that the level of progerin expression correlates with severity of disease.
Scaffidi and Misteli (2008) found that progerin (150330.0022) expression in immortalized human skin fibroblasts produced several defects typical of HGPS. Progerin also caused the spontaneous differentiation of human mesenchymal stem cells (MSCs) into endothelial cells, and reduced their differentiation along the adipogenic lineage. Abnormal differentiation of MSCs appeared to be due to progerin-induced activation of major downstream effectors of the Notch signaling pathway, including HES1 (139605), HES5 (607348), and HEY1 (602953). Scaffidi and Misteli (2008) noted that the progerin splice variant of LMNA is present at low levels in cells from healthy individuals and has been implicated in the normal aging process. They suggested that progerin-induced defects in Notch signaling are involved in normal aging and similarly affect adult MSCs and their differentiation.
In affected members of a nonconsanguineous family with an atypical form of HGPS manifest as adult-onset coronary disease and progeroid features, Hisama et al. (2011) identified a heterozygous splice site mutation affecting exon 11 of the LMNA gene (c.1968G-A; 150330.0055). An unrelated patient with a similar disorder carried a different splice site mutation that also affected exon 11 (C.1968+5G-A; 150330.0056). Patient cells in both cases showed the presence of progerin at lower levels than observed in typical HGPS cells. The report illustrated the evolving genotype/phenotype relationship between the amount of progerin produced and the age of onset of the spectrum of clinical features associated with LMNA-associated progeroid syndromes.
In affected members of a family with a protracted form of HGPS (see 176670) manifest as premature cutaneous and cardiac aging in young adulthood, Kane et al. (2013) identified a heterozygous missense mutation in the LMNA gene (D300G; 150330.0057). Skin fibroblasts derived from the proband showed abnormal morphology, including blebs, lobulation, and ringed or donut-shaped nuclei. Although the processing of lamin A and C were normal in patient cells, treatment with farnesyltransferase inhibitors resulted in improved nuclear morphology. Overexpression of the mutation in control fibroblasts led to abnormal nuclear morphology in a dominant-negative manner.
Restrictive Dermopathy 2
In 2 of 9 patients with restrictive dermopathy (RSMD2; 619793), a lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence, Navarro et al. (2004) identified heterozygous splicing mutations in the LMNA gene, resulting in the complete or partial loss of exon 11 (150330.0036 and 150330.0022, respectively). In the other 7 patients, they identified a heterozygous 1-bp duplication resulting in a premature stop codon in the zinc metalloproteinase STE24 gene (ZMPSTE24; 606480). This gene encodes a metalloproteinase specifically involved in the posttranslational processing of lamin A precursor. In all patients carrying a ZMPSTE24 mutation, loss of expression of lamin A as well as abnormal patterns of nuclear sizes and shapes and mislocalization of lamin-associated proteins was seen. Navarro et al. (2004) concluded that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in restrictive dermopathy.
Navarro et al. (2005) described 7 previously reported patients and 3 new patients with restrictive dermopathy who were homozygous or compound heterozygous for ZMPSTE24 mutations. In all cases there was complete absence of both ZMPSTE24 and mature lamin A, associated with prelamin A accumulation. The authors concluded that restrictive dermopathy is either a primary or a secondary laminopathy, caused by dominant de novo LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations. The accumulation of truncated or normal length prelamin A is, therefore, a shared pathophysiologic feature in recessive and dominant restrictive dermopathy.
Heart-Hand Syndrome, Slovenian Type
In a Slovenian family with heart-hand syndrome (610140), originally reported by Sinkovec et al. (2005), Renou et al. (2008) identified a splice site mutation in the LMNA gene (150330.0045) that segregated with disease and was not found in 100 healthy controls. Analysis of fibroblasts from 2 affected members of the family revealed truncated lamin A/C protein and nuclear envelope abnormalities, confirming the pathogenicity of the mutation.
In affected members of a family with Slovenian-type heart-hand syndrome, Zaragoza et al. (2017) identified heterozygosity for a missense mutation in the LMNA gene (R335W; 150330.0058) that segregated with the disorder in the family. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
Other Associations
Hegele et al. (2000) identified a common single-nucleotide polymorphism (SNP) in LMNA, 1908C/T, which was associated with obesity-related traits in Canadian Oji-Cree. Hegele et al. (2001) reported association of this LMNA SNP with anthropometric indices in 186 nondiabetic Canadian Inuit. They found that physical indices of obesity, such as body mass index, waist circumference, waist-to-hip circumference ratio, subscapular skinfold thickness, and subscapular-to-triceps skinfold thickness ratio were each significantly higher among Inuit subjects with the LMNA 1908T allele than in subjects with the 1908C/1908C genotype. For each significantly associated obesity-related trait, the LMNA 1908C/T SNP genotype accounted for approximately 10 to 100% of the attributable variation. The results indicated that common genetic variation in LMNA is an important determinant of obesity-related quantitative traits.
In 14 of 15 families with familial partial lipodystrophy, Speckman et al. (2000) identified mutations in exon 8 of the LMNA gene: 5 families had an R482Q mutation (150330.0010); 7 families had an R482W alteration (150330.0011), and 1 family had a G465D alteration (150330.0015). The R482Q and R482W mutations occurred on different haplotypes, indicating that they probably had arisen more than once. One family with an atypical form of familial partial lipodystrophy had an R582H mutation (150330.0016) in exon 11 of the LMNA gene, which the authors noted can affect the lamin A protein only. Speckman et al. (2000) noted that all mutations in Dunnigan lipodystrophy affect the globular C-terminal domain of the lamin A/C protein, whereas mutations responsible for dilated cardiomyopathy and conduction-system disease are usually clustered in the rod domain of the protein (Fatkin et al., 1999). Speckman et al. (2000) could not detect mutations in the LMNA gene in 1 FPLD family that showed linkage to 1q21-q23.
Hegele (2005) used hierarchical cluster analysis to assemble 16 laminopathy phenotypes into 2 classes based on organ system involvement, and then classified 91 reported causative LMNA mutations according to their position upstream or downstream of the nuclear localization signal (NLS) sequence. Contingency analysis revealed that laminopathy class and LMNA mutation position were strongly correlated (p less than 0.0001), suggesting that laminopathy phenotype and LMNA genotype are nonrandomly associated.
Lanktree et al. (2007) analyzed the LMNA gene in 3 unrelated patients with FPLD2 and identified heterozygosity for 3 different missense mutations, all affecting only the lamin A isoform and each changing a conserved residue. Two of the mutations, D230N (150330.0042) and R399C (150330.0043), were 5-prime to the NLS, which is not typical of LMNA mutations in FPLD2. The third mutation, S573L (150330.0041), had previously been identified in heterozygosity in a patient with dilated cardiomyopathy and conduction defects (CMD1A; 115200) and in homozygosity in a patient with arthropathy, tendinous calcinosis, and progeroid features (see 248370). None of the mutations were found in 200 controls of multiple ethnicities. Because heterozygosity for an S573L mutation can cause cardiomyopathy without lipodystrophy or lipodystrophy without cardiomyopathy, Lanktree et al. (2007) suggested that additional factors, genetic or environmental, may contribute to the precise tissue involvement.
Gupta et al. (2010) analyzed the LMNA gene in heart samples from 25 unrelated CMD patients and identified 3 heterozygous missense mutations in 3 patients as well as a heterozygous deletion of exons 3 to 12 in 1 patient. The LMNA deletion and 1 of the missense mutations were associated with major cardiomyocyte nuclear envelope abnormalities, whereas the other 2 missense mutations were found in patients without specific nuclear envelope abnormalities. Gupta et al. (2010) stated that they did not find any evidence of a genotype/phenotype relationship between the onset and severity of CMD, the presence of nuclear abnormalities, and the presence or absence of LMNA mutations.
Barthelemy et al. (2015) analyzed LMNA exon 11 transcripts in cells derived from patients with atypical progeroid syndromes associated with heterozygous mutations affecting the splicing of exon 11 of the LMNA gene (150330.0036, 150330.0055, and 150330.0056). All cells carried a normal full-length prelamin A transcript, a band corresponding to prelamin A(del50) (progerin), and an additional transcript corresponding to prelamin A(del90) resulting from the skipping of all of exon 11. Barthelemy et al. (2015) termed the prelamin A(del90) transcript 'dermopathin' because it was first observed in a patient with restrictive dermopathy (619793) by Navarro et al. (2004) (see 150330.0036). Dermopathin excludes the 270 nucleotides of exon 11 and is predicted to cause an internal deletion preserving the prelamin A open reading frame (Gly567_Gln656del). The findings indicated that progerin accumulation is the major pathogenetic mechanism responsible for HGPS-like disorders due to LMNA mutations.
Mounkes et al. (2003) attempted to create a mouse model for autosomal dominant Emery-Dreifuss muscular dystrophy (181350) by introducing a L530P (150330.0004) mutation in the LMNA gene. Although mice heterozygous for L530P did not show signs of muscular dystrophy and remained overtly normal up to 6 months of age, mice homozygous for the mutation showed phenotypes markedly reminiscent of symptoms observed in progeria patients. Homozygous Lmna L530P/L530P mice were indistinguishable from their littermates at birth, but by 4 to 6 days developed severe growth retardation, dying within 4 to 5 weeks. Homozygous mutant mice showed a slight waddling gait, suggesting immobility of joints. Other progeria features of these mutant mice included micrognathia and abnormal dentition--in approximately half of the mutants a gap was observed between the lower 2 incisors, which also appeared yellowed. Mutant mice also had loss of subcutaneous fat, reduced numbers of eccrine and sebaceous glands, increased collagen deposition in skin, and decreased hair follicle density. Mounkes et al. (2003) concluded that Lmna L530P/L530P mice have significant phenotypic overlap with Hutchinson-Gilford progeria syndrome, including nuclear envelope abnormalities and decreased doublet capacity and life span of fibroblasts.
Mounkes et al. (2005) generated mice expressing the human N195K (150330.0007) mutation and observed characteristics consistent with CMD1A. Continuous electrocardiographic monitoring of cardiac activity demonstrated that N195K-homozygous mice died at an early age due to arrhythmia. Immunofluorescence and Western blot analysis showed that Hf1b/Sp4 (600540), connexin-40 (GJA5; 121013), and connexin-43 (GJA1; 121014) were misexpressed and/or mislocalized in N195K-homozygous mouse hearts. Desmin staining revealed a loss of organization at sarcomeres and intercalated disks. Mounkes et al. (2005) hypothesized that mutations within the LMNA gene may cause cardiomyopathy by disrupting the internal organization of the cardiomyocyte and/or altering the expression of transcription factors essential to normal cardiac development, aging, or function.
Arimura et al. (2005) created a mouse model of autosomal dominant Emery-Dreifuss muscular dystrophy expressing an H222P mutation in Lmna. At adulthood, male homozygous mice displayed reduced locomotion activity with abnormal stiff walking posture, and all died by 9 months of age. They also developed dilated cardiomyopathy with hypokinesia and conduction defects. These skeletal and cardiac muscle features were also observed in the female homozygous mice, but with a later onset than in males. Histopathologic analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signaling in heart and skeletal muscles.
Varga et al. (2006) created transgenic mice carrying the G608G (150330.0022)-mutated human LMNA gene and observed the development of a dramatic defect of the large arteries, consisting of progressive medial vascular smooth muscle cell loss and replacement with proteoglycan and collagen followed by vascular remodeling with calcification and adventitial thickening. In vivo, these arterial abnormalities were reflected by a blunted initial response to the vasodilator sodium nitroprusside, consistent with impaired vascular relaxation, and attenuated blood pressure recovery after infusion. Varga et al. (2006) noted that although G608G transgenic mice lacked the external phenotype seen in human progeria, they demonstrated a progressive vascular abnormality that closely resembled the most lethal aspect of the human phenotype.
Frock et al. (2006) found that most cultured muscle cells from Lmna knockout mice exhibited impaired differentiation kinetics and reduced differentiation potential. Similarly, knockdown of Lmna or emerin (EMD; 300384) expression by RNA interference in normal muscle cells impaired differentiation potential and reduced expression of muscle-specific genes, Myod (159970) and desmin (125660). To determine whether impaired myogenesis was linked to reduced Myod or desmin levels, Frock et al. (2006) individually expressed these proteins in Lmna-null myoblasts and found that both increased the differentiation potential of mutant myoblasts. Frock et al. (2006) concluded that LMNA and emerin are required for myogenic differentiation, at least in part, through an effect on expression of critical myoblast proteins.
Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production of a truncated prelamin A, called progerin, which is farnesylated at its C terminus and accumulates at the nuclear envelope, causing misshapen nuclei (Yang et al., 2006). Farnesyltransferase inhibitors (FTIs) have been shown to reverse this cellular abnormality (Yang et al., 2005; Toth et al., 2005; Capell et al., 2005; Mallampalli et al., 2005). Yang et al. (2006) generated mice with a targeted HGPS mutation (Lmna HG/+) and observed phenotypes similar to those in human HGPS patients, including retarded growth, reduced amounts of adipose tissue, micrognathia, osteoporosis, and osteolytic lesions in bone, which caused spontaneous rib fractures in the mutant mice. Treatment with an FTI increased adipose tissue mass, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness.
Yang et al. (2008) created knockin mice expressing a nonfarnesylatable form of progerin. Knockin mice developed the same disease phenotype as mice expressing farnesylated progerin, although the phenotype was milder, and embryonic fibroblasts derived from these mice contained fewer misshapen nuclei. The steady-state level of nonfarnesylated progerin, but not mRNA, was lower in cultured fibroblasts and whole tissues, suggesting that the absence of farnesylation may accelerate progerin turnover.
In a mouse model of EDMD carrying an H222P mutation in the Lmna gene (Arimura et al., 2005), Muchir et al. (2007) found that activation of MAPK (see 176948) pathways preceded clinical signs or detectable molecular markers of cardiomyopathy. Expression of H222P-mutant Lmna in heart tissue and isolated cardiomyocytes resulted in tissue-specific activation of MAPKs and downstream target genes. The results suggested that activation of MAPK pathways plays a role in the pathogenesis of cardiac disease in EDMD.
Muchir et al. (2009) demonstrated abnormal activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) signaling cascade in hearts of Lmna H222P knockin mice, a model of autosomal Emery-Dreifuss muscular dystrophy. Systemic treatment of Lmna H222P/H222P mice that developed cardiomyopathy with PD98059, an inhibitor of ERK activation, inhibited ERK phosphorylation and blocked the activation of downstream genes in heart. It also blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere organization that occurred in placebo-treated mice. Histologic analysis and echocardiography demonstrated that treatment with PD98059 delayed the development of left ventricular dilatation. PD98059-treated Lmna H222P/H222P mice had normal cardiac ejection fractions assessed by echocardiography, whereas placebo-treated mice had a 30% decrease. The authors emphasized the role of ERK activation in the development of cardiomyopathy caused by LMNA mutations, and provided further proof of principle for ERK inhibition as a therapeutic option to prevent or delay heart failure in humans with Emery-Dreifuss muscular dystrophy and related disorders caused by mutations in LMNA.
Davies et al. (2010) created knockin mice harboring a mutant Lmna allele that yielded exclusively nonfarnesylated prelamin A. These mice had no evidence of progeria but succumbed to cardiomyopathy. Most of the nonfarnesylated prelamin A in the tissues of these mice was localized at the nuclear rim, indistinguishable from the lamin A in wildtype mice. The cardiomyopathy could not be ascribed to an absence of lamin C because mice expressing an otherwise identical knockin allele yielding only wildtype prelamin A appeared normal. The authors concluded that lamin C synthesis is dispensable in mice and that failure to convert prelamin A to mature lamin A causes cardiomyopathy in the absence of lamin C.
Choi et al. (2012) found that ERK activation in H222P/H222P mice specifically upregulated expression of dual-specificity phosphatase-4 (DUSP4; 602747) in cardiac muscle, with much lower Dusp4 induction in quadriceps muscle, and no Dusp4 induction in tongue, kidney, and liver. Dusp4 overexpression in cultured C2C12 muscle cells or targeted to mouse heart resulted in activation of the Akt (see AKT1; 164730)-Mtor (FRAP1; 601231) metabolic signaling pathway, leading to impaired autophagy and abnormal cardiac metabolism, similar to findings in H222P/H222P mice.
Thomasson et al. (2019) found that mice homozygous for the Lmna H222P mutation had depressed left ventricular function and altered body composition. The mutation decreased metabolic performance in mice and changed their physical activity. Supplementation with nicotinamide riboside (NR) in the diet partially restored the structure and function of striated muscles and improved the performance of mutant mice.
Wang et al. (2022) generated mice homozygous for a leu648-to-arg (L648R) mutation in Lmna, corresponding to the HGPS-causing L647R mutation in human LMNA that abolishes the prelamin A ZMPSTE24 cleavage site. Homozygous mutant mice expressed prelamin A and lamin C at roughly the same levels as wildtype, but they lacked mature lamin A. Mutant mice were viable, fertile, and grossly indistinguishable compared with wildtype, but they had unexpectedly long lifespans and low body mass and body fat. Microcomputed tomographic analysis revealed that homozygous mutant mice had cranial and mandibular defects with dental abnormalities, resembling those of Zmpste24 -/- mice and humans with HGPS mutations, but they appeared to be less severe and were not prominent until later in life. Mutant mice also exhibited decreased vertebral bone density and long bone defects, similar to Zmpste24 -/- mice, but they had normal grip strength with only rare rib fractures at old, preterminal ages. Analysis of embryonic fibroblasts from the mutant mice showed an accumulation of prelamin A and abnormal nuclear morphology, suggesting that accumulation of the farnesylated form of prelamin A was responsible for abnormal nuclear morphology.
In a family with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), Bonne et al. (1999) identified a C-to-T transition in exon 1 of the LMNA gene that changed glutamine-6 (CAG) to a stop codon (TAG).
In a family with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), Bonne et al. (1999) demonstrated a C-to-T transition in exon 7 of the LMNA gene, resulting in an arg453-to-trp (R453W) substitution.
In 2 families with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), Bonne et al. (1999) found a G-to-C transversion in the LMNA gene which, resulting in an arg527-to-pro (R527P) substitution. The mutation, found in heterozygous state, was demonstrated to be de novo in both families.
Van der Kooi et al. (2002) reported a woman with limb-girdle muscle weakness, spinal rigidity, contractures, elevated creatine kinase, cardiac conduction abnormalities (atrial fibrillation), partial lipodystrophy (151660), and increased serum triglycerides who had the R527P mutation. Van der Kooi et al. (2002) also reported a family with the R527P mutation in which the proband, her father, and her son all presented with varying degrees of EDMD, lipodystrophy, and cardiac conduction abnormalities.
Makri et al. (2009) reported 2 sisters with early-onset autosomal dominant muscular dystrophy most consistent with EDMD. Because the girls were born of consanguineous Algerian parents, they were at first thought to have an autosomal recessive congenital muscular dystrophy. However, genetic analysis identified a heterozygous R527P mutation in the LMNA gene in both patients that was not present in either unaffected parent. The results were consistent with germline mosaicism or a recurrent de novo event. The older sib had a difficult birth and showed congenital hypotonia, diffuse weakness, and mild initial respiratory and feeding difficulties. She sat unsupported at age 2 years and walked independently from age 4 years with frequent falls and a waddling gait. At 13 years she had a high-arched palate, moderate limb hypotonia, and weakness of the pelvic muscles. There was proximal limb wasting, moderate cervical, elbow, and ankle contractures, pes cavus, spinal rigidity, and lordosis/scoliosis. Her sister had mild hypotonia in early infancy, walked without support at 24 months, and showed proximal muscle weakness. There were mild contractures of the elbow and ankles. At age 9 years, she showed adiposity of the neck, trunk and abdomen, consistent with lipodystrophy. Brain MRI and cognition were normal in both sisters, and neither had cardiac involvement. Muscle biopsies showed a dystrophic pattern.
In a family with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), Bonne et al. (1999) detected a heterozygous T-to-C transition in the LMNA gene, resulting in a leu530-to-pro (L530P) substitution.
Dilated Cardiomyopathy 1A
In a family with autosomal dominant dilated cardiomyopathy with conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a 178C-G transversion in the LMNA gene, resulting in an arg60-to-gly (R60G) substitution.
Familial Partial Lipodystrophy, Type 2
Van der Kooi et al. (2002) reported a woman with partial lipodystrophy (FPLD2; 151660), hypertriglyceridemia, and cardiomyopathy with conduction defects who carried the R60G mutation. The patient's mother reportedly had similar manifestations. The authors noted that lipodystrophy and cardiac abnormalities were combined manifestations of the same mutation.
In a family with autosomal dominant dilated cardiomyopathy with conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a 254T-G transversion in the LMNA gene, resulting in a leu85-to-arg (L85R) substitution.
In a family with autosomal dominant dilated cardiomyopathy with conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a 585C-G transversion in the LMNA gene, resulting in an asn195-to-lys (N195K) substitution.
Variant Function
Using cells from the mouse model of Mounkes et al. (2005), Ho et al. (2013) found that Lmna N195K embryonic fibroblasts and bone marrow-derived mesenchymal stem cells had impaired nuclear localization of the mechanosensitive transcription factor MKL1 (606078). Cardiac sections from Lmna(N195K/N195K) mice had significantly reduced fractions of cardiomyocytes with nuclear Mkl1, implicating altered Mkl1 signaling in the development of cardiomyopathy in these animals. Nuclear accumulation of Mkl1 was substantially lower in Lmna N195K cells than in wildtype cells. Altered nucleocytoplasmic shuttling of Mkl1 was caused by altered actin dynamics in Lmna(N195K/N195K) mutant cells. Ectopic expression of the nuclear envelope protein emerin (300384) restored Mkl1 nuclear translocation and rescued actin dynamics in mutant cells.
In a family with autosomal dominant dilated cardiomyopathy with conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a 608A-G transition in the LMNA gene, resulting in a glu203-to-gly (E203G) substitution.
In a family with autosomal dominant dilated cardiomyopathy and conduction defects (CMD1A; 115200), Fatkin et al. (1999) identified a 1711C-A transversion in the LMNA gene, resulting in an arg571-to-ser (R571S) substitution. In this family, the C-terminal of lamin C was selectively affected by the mutation, and the cardiac phenotype was relatively milder than that associated with mutations in the rod domain of the LMNA gene. Furthermore, there was subclinical evidence of involvement of skeletal muscle. Although affected members of this family had no skeletal muscle symptoms, some had elevated serum creatine kinase levels, including 1 asymptomatic family member with the genotype associated with the disease. The arg571-to-ser mutation affected only lamin C isoforms, whereas previously described defects causing Emery-Dreifuss muscular dystrophy (181350) perturbed both lamin A and lamin C isoforms.
In 5 probands from 5 Canadian kindreds with familial partial lipodystrophy of the Dunnigan type (FPLD2; 151660), Cao and Hegele (2000) demonstrated heterozygosity for a G-to-A transition in exon 8 of the LMNA gene, predicted to result in an arg484-to-gln (R482Q) substitution. There were no differences in age, gender, or body mass index in Q482/R482 heterozygotes compared with R482/R482 homozygotes (normals) from these families; however, there were significantly more Q482/R482 heterozygotes who had definite partial lipodystrophy and frank diabetes. Also compared with the normal homozygotes, heterozygotes had significantly higher serum insulin and C-peptide (see 176730) levels. The LMNA heterozygotes with diabetes were significantly older than heterozygotes without diabetes.
Shackleton et al. (2000) found the R482Q mutation in a family with familial partial lipodystrophy. Hegele et al. (2000) analyzed the relationship between plasma leptin (164160) and the rare LMNA R482Q mutation in 23 adult familial partial lipodystrophy (FPLD) subjects compared with 25 adult family controls with normal LMNA in an extended Canadian FPLD kindred. They found that the LMNA Q482/R482 genotype was a significant determinant of plasma leptin, the ratio of plasma leptin to body mass index (BMI), plasma insulin, and plasma C peptide, but not BMI. Family members who were Q482/R482 heterozygotes had significantly lower plasma leptin and leptin:BMI ratio than unaffected R482/R482 homozygotes. Fasting plasma concentrations of insulin and C peptide were both significantly higher in LMNA Q482/R482 heterozygotes than in R482/R482 homozygotes. Multivariate regression analysis revealed that the LMNA R482Q genotype accounted for 40.9%, 48.2%, 86.9%, and 81.0%, respectively, of the attributable variation in log leptin, leptin:BMI ratio, log insulin, and log C peptide. The authors concluded that a rare FPLD mutation in LMNA determines the plasma leptin concentration.
Boguslavsky et al. (2006) found that overexpression of wildtype LMNA or mutant R482Q or R482W (150330.0011) in mouse 3T3-L1 preadipocytes prevented cellular lipid accumulation, inhibited triglyceride synthesis, and prevented normal differentiation into adipocytes. In contrast, embryonic fibroblasts from Lmna-null mice had increased levels of basal triglyceride synthesis and differentiated into fat-containing cells more readily that wildtype mouse cells. Mutations at residue 482 are not predicted to affect the structure of the nuclear lamina, but may change interactions with other proteins. The findings of this study suggested that mutations responsible for FPLD are gain-of-function mutations. Boguslavsky et al. (2006) postulated that mutations that result in gain of function may cause higher binding affinity to a proadipogenic transcription factor, thus preventing it from activating target genes; overexpression of the wildtype protein may result in increased numbers of molecules with a normal binding affinity. Overexpression of Lmna was associated with decreased levels of PPARG2 (601487), a nuclear hormone receptor transcription factor putatively involved in adipogenic conversion. Lmna-null cells had increased basal phosphorylation of AKT1 (164730), a mediator of insulin signaling.
In affected members of a Hutterite family with FPLD2, Wiltshire et al. (2013) identified a heterozygous R482Q mutation. Two family members were homozygous for the mutation and presented with onset of autosomal recessive Emery-Dreifuss muscular dystrophy-3 (EDMD3; 616516) as well as partial lipodystrophy in the first or second decades. The findings expanded the phenotype associated with this mutation. The overall frequency of the mutation in Dariusleut and Lehrerleut Hutterites in Alberta, Canada, was found to be 1.45%.
In 6 families and 3 isolated cases of partial lipodystrophy (FPLD2; 151660), Shackleton et al. (2000) found heterozygosity for C-to-T transition in the LMNA gene, resulting in an arg482-to-trp (R482W) substitution. This is the same codon as that affected in the R482Q mutation (150330.0010). R482L (150330.0012) is a third mutation in the same codon causing partial lipodystrophy.
Schmidt et al. (2001) identified a family with partial lipodystrophy carrying the R482W mutation in the LMNA gene. Clinically, the loss of subcutaneous fat and muscular hypertrophy, especially of the lower extremities, started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. Characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. In conclusion, dyslipidemia is an early and prominent feature in the presented lipodystrophic family carrying the R482W mutation.
Vadrot et al. (2015) stated that R482 is located within the Ig fold common to A-type lamins, and found that the Ig fold is involved in binding of A-type lamins to SREBP1. In overexpression studies in primary human preadipocytes and patient fibroblasts, Vadrot et al. (2015) found that the R482W substitution reduced the inhibitory interaction of mutant LMNA with SREBP1. R482W patient fibroblasts showed elevated SREBP1 transcriptional activity and derepression of a large number of SREBP1 target genes.
In a family with partial lipodystrophy (FPLD2; 151660), Shackleton et al. (2000) found that the affected individuals were heterozygous for a G-to-T transversion in the LMNA gene, resulting in an arg482-to-leu (R482L) substitution.
In a large family with a severe autosomal dominant dilated cardiomyopathy with conduction defects (CMD1A; 115200) in which the majority of affected family members showed signs of mild skeletal muscle involvement, Brodsky et al. (2000) demonstrated heterozygosity in affected members for a 1-bp deletion (del959T) deletion in exon 6 of the LMNA gene. One individual had a pattern of skeletal muscle involvement that the authors considered consistent with mild Emery-Dreifuss muscular dystrophy (EDMD2; 181350).
In a 40-year-old man with autosomal recessive Emery-Dreifuss muscular dystrophy-3 (EDMD3; 616516), Raffaele di Barletta et al. (2000) found a homozygous 664C-T transition in the LMNA gene, resulting in a his222-to-tyr (H222Y) amino acid substitution. Both parents, who were first cousins, were heterozygous for the mutation and were unaffected. The mutation was not found among 200 control chromosomes. The patient was the only one with a homozygous LMNA mutation among a larger study of individuals with autosomal dominant Emery-Dreifuss muscular dystrophy.
Speckman et al. (2000) found that 1 of 15 families with familial partial lipodystrophy of the Dunnigan variety (FPLD2; 151660) harbored a gly465-to-asp (G465D) mutation in exon 8 of the LMNA gene.
Simon et al. (2013) noted that G465 is located at the 'bottom front' of the Ig-fold of the mature lamin A tail. They found that the G465D substitution reduced SUMO1 (601912), but not SUMO2 (603042), modification of the lamin A tail in vitro and in cells.
In a family with an atypical form of familial partial lipodystrophy (FPLD2; 151660), Speckman et al. (2000) identified an arg582-to-his (R582H) mutation in exon 11 of the LMNA gene. In a follow-up of this same family, Garg et al. (2001) reported that 2 affected sisters showed less severe loss of subcutaneous fat from the trunk and extremities with some retention of fat in the gluteal region and medial parts of the proximal thighs compared to women with typical FPLD2. Noting that the R582H mutation interrupts only the lamin A protein, Garg et al. (2001) suggested that in typical FPLD2, interruption of both lamins A and C causes a more severe phenotype than that seen in atypical FPLD2, in which only lamin A is altered.
In a family (family C) diagnosed with limb-girdle muscular dystrophy type 1B (LGMD1B), which was reclassified as Emery-Dreifuss muscular dystrophy-2 (EDMD2; 181350) by Straub et al. (2018), Muchir et al. (2000) found a G-to-A transition in exon 6 of the LMNA gene, resulting in a substitution of histidine for arginine-377 (R377H). This family was previously reported by van der Kooi et al. (1996, 1997).
Taylor et al. (2003) identified heterozygosity for the R377H mutation in an American family of British descent with autosomal dominant dilated cardiomyopathy and mild limb-girdle muscular disease.
Charniot et al. (2003) described a French family with autosomal dominant severe dilated cardiomyopathy with conduction defects or atrial/ventricular arrhythmias and a skeletal muscular dystrophy of the quadriceps muscles. Affected members were found to carry the R377H mutation, which was shown by transfection experiments in both muscular and nonmuscular cells to lead to mislocalization of both lamin and emerin (300384). Unlike previously reported cases of LMNA mutations causing dilated cardiomyopathy with neuromuscular involvement, cardiac involvement preceded neuromuscular disease in all affected members. Charniot et al. (2003) suggested that factors other than the R377H mutation influenced phenotypic expression in this family. Sebillon et al. (2003) also reported on this family.
In a German woman who had been diagnosed with LGMD1B, Rudnik-Schoneborn et al. (2007) identified a heterozygous R377H mutation in the LMNA gene. Family history revealed that the patient's paternal grandmother had proximal muscle weakness and died from heart disease at age 52, and a paternal aunt had 'walking difficulties' since youth. The patient's father and 4 cousins all had cardiac disease without muscle weakness ranging from nonspecific 'heart attacks' to dilated cardiomyopathy and arrhythmia. The only living affected cousin also carried the mutation.
In a family (family A) diagnosed with limb-girdle muscular dystrophy type 1B (LGMD1B), which was reclassified as Emery-Dreifuss muscular dystrophy-2 (EDMD2; 181350) by Straub et al. (2018), Muchir et al. (2000) found a 3-bp deletion (AAG) in exon 3 of the LMNA gene, resulting in loss of the codon for lysine-208 (delK208). This family was previously reported by van der Kooi et al. (1996, 1997).
In a family (family B) diagnosed with limb-girdle muscular dystrophy type 1B (LGMD1B), which was reclassified as Emery-Dreifuss muscular dystrophy-2 (EDMD2; 181350) by Straub et al. (2018), Muchir et al. (2000) found a G-to-C transversion in the splice donor site of intron 9, leading to retention of intron 9 and a frameshift at position 536. This potentially results in a truncated protein lacking half of the globular tail domain of lamins A/C. This family was previously reported by van der Kooi et al. (1996, 1997).
De Sandre-Giovannoli et al. (2002) found a homozygous arg298-to-cys (R298C) mutation in the LMNA gene in affected members of Algerian families with axonal Charcot-Marie-Tooth disease type 2B1 (CMT2B1; 605588).
Ben Yaou et al. (2007) identified a homozygous R298C mutation in a female and 2 male affected members of an Algerian family with CMT2B1. The 2 males also had X-linked Emery-Dreifuss muscular dystrophy (310300) and a hemizygous mutation in the EMD gene (300384).
In 5 consanguineous Italian families, Novelli et al. (2002) demonstrated that individuals with mandibuloacral dysplasia (MADA; 248370) were homozygous for an arg527-to-his (R527H) mutation.
In affected members from 2 pedigrees with MADA, Simha et al. (2003) identified the homozygous R527H mutation.
In a Mexican American boy with MADA born of related parents, Shen et al. (2003) identified homozygosity for the R527H mutation. The authors noted that all the patients reported by Novelli et al. (2002) shared a common disease haplotype, but that the patients reported by Simha et al. (2003) and their Mexican American patient had different haplotypes, indicating independent origins of the mutation. The mutation is located within the C-terminal immunoglobulin-like domain in the center of a beta sheet on the domain surface of the protein.
Lombardi et al. (2007) identified this mutation in compound heterozygosity with another missense mutation (V440M; 150330.0044) in a patient with an apparent MADA phenotype associated with muscular hyposthenia and generalized hypotonia.
Garavelli et al. (2009) reported 2 unrelated patients with early childhood onset of MADA features associated with a homozygous R527H mutation. One presented at age 5 years, 3 months with bulbous distal phalanges of fingers and was observed to have dysmorphic craniofacial features, lipodystrophy type A, and acroosteolysis. The second child, born of consanguineous Pakistani parents, presented at age 4 years, 2 months with a round face, chubby cheeks, thin nose, lipodystrophy type A, and short, broad distal phalanges. Garavelli et al. (2009) emphasized that features of this disorder may become apparent as early as preschool age and that bulbous fingertips may be a clue to the diagnosis.
Hutchinson-Gilford Progeria Syndrome
In 18 of 20 patients with classic Hutchinson-Gilford progeria syndrome (HGPS; 176670), Eriksson et al. (2003) found an identical de novo 1824C-T transition, resulting in a silent gly-to-gly mutation at codon 608 (G608G) within exon 11 of the LMNA gene. This substitution created an exonic consensus splice donor sequence and results in activation of a cryptic splice site and deletion of 50 codons of prelamin A. This mutation was not identified in any of the 16 parents available for testing.
De Sandre-Giovannoli et al. (2003) identified the exon 11 cryptic splice site activation mutation (1824C-T+1819-1968del) in 2 HGPS patients. Immunocytochemical analyses of lymphocytes from 1 patient using specific antibodies directed against lamin A/C, lamin A, and lamin B1 showed that most cells had strikingly altered nuclear sizes and shapes, with envelope interruptions accompanied by chromatin extrusion. Lamin A was detected in 10 to 20% of HGPS lymphocytes. Only lamin C was present in most cells, and lamin B1 was found in the nucleoplasm, suggesting that it had dissociated from the nuclear envelope due to the loss of lamin A. Western blot analysis showed 25% of normal lamin A levels, and no truncated form was detected.
Cao and Hegele (2003) confirmed the observations of Eriksson et al. (2003) using the same cell lines. They referred to this mutation as 2036C-T.
D'Apice et al. (2004) confirmed paternal age effect and demonstrated a paternal origin of the 2036C-T mutation in 3 families with isolated cases of Hutchinson-Gilford progeria.
By light and electron microscopy of fibroblasts from HGPS patients carrying the 1824C-T mutation, Goldman et al. (2004) found significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsened as the HGPS cells aged in culture, and their severity correlated with an apparent accumulation of mutant protein, which Goldman et al. (2004) designated LA delta-50. Introduction of LA delta-50 into normal cells by transfection or protein injection induced the same changes. Goldman et al. (2004) hypothesized that the alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LA delta-50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication.
In a patient with Hutchinson-Gilford progeria, Wuyts et al. (2005) identified the G608G mutation. In lymphocyte DNA from the parents, normal wildtype alleles were observed in the father, but a low signal corresponding to the mutant allele was detected in the mother's DNA. A segregation study confirmed that the patient's mutation was transmitted from the mother, who showed germline and somatic mosaicism without manifestations of HGPS.
Glynn and Glover (2005) studied the effects of farnesylation inhibition on nuclear phenotypes in cells expressing normal and G608G-mutant lamin A. Expression of a GFP-progerin fusion protein in normal fibroblasts caused a high incidence of nuclear abnormalities (as seen in HGPS fibroblasts), and resulted in abnormal nuclear localization of GFP-progerin in comparison with the localization pattern of GFP-lamin A. Expression of a GFP-lamin A fusion containing a mutation preventing the final cleavage step, which caused the protein to remain farnesylated, displayed identical localization patterns and nuclear abnormalities as in HGPS cells and in cells expressing GFP-progerin. Exposure to a farnesyltransferase inhibitor (FTI), PD169541, caused a significant improvement in the nuclear morphology of cells expressing GFP-progerin and in HGPS cells. Glynn and Glover (2005) proposed that abnormal farnesylation of progerin may play a role in the cellular phenotype in HGPS cells, and suggested that FTIs may represent a therapeutic option for patients with HGPS.
In cells from a female patient with HGPS due to the 1824C-T mutation, Shumaker et al. (2006) found that the inactive X chromosome showed loss of histone H3 trimethylation of lys27 (H3K27me3), a marker for facultative heterochromatin, as well as loss of histone H3 trimethylation of lys9 (H3K9me3), a marker of pericentric constitutive heterochromatin. Other alterations in epigenetic control included downregulation of the EZH2 methyltransferase (601573), upregulation of pericentric satellite III repeat transcripts, and increase in the trimethylation of H4K20. The epigenetic alterations were observed before the pathogenic changes in nuclear shape. The findings indicated that the mutant LMNA protein alters sites of histone methylation known to regulate heterochromatin and provided evidence that the rapid aging phenotype of HGPS reflects aspects of normal aging at the molecular level.
Moulson et al. (2007) demonstrated that HGPS cells with the common 1824C-T LMNA mutation produced about 37.5% of wildtype full-length transcript, which was higher than previous estimates (Reddel and Weiss, 2004).
Using real-time RT-PCR, Rodriguez et al. (2009) found that progerin transcripts were expressed in dermal fibroblasts cultured from normal controls, but at a level more than 160-fold lower than that detected in dermal fibroblasts cultured from HGPS patients. The level of progerin transcripts, but not of lamin A or lamin C transcripts, increased in late-passage cells from both normal controls and HGPS patients.
Restrictive Dermopathy 2
In an infant (P2) with restrictive dermopathy (RSDM2; 619793), Navarro et al. (2004) identified the 1824C-T transition in the LMNA gene in heterozygous state.
In a patient with Hutchinson-Gilford progeria syndrome (HGPS; 176670), Eriksson et al. (2003) identified a G-to-A transition in the LMNA gene resulting in a gly-to-ser substitution at codon 608 (G608S). This mutation was not identified in either parent.
Cao and Hegele (2003) confirmed the observation of Eriksson et al. (2003) using the same cell line.
In a patient with somewhat atypical features of Hutchinson-Gilford progeria syndrome (HGPS; 176670), Eriksson et al. (2003) identified a glu-to-lys substitution at codon 145 (E145K) in exon 2 of the LMNA gene. This mutation was not identified in either parent. Atypical clinical features, including persistence of coarse hair over the head, ample subcutaneous tissue over the arms and legs, and severe strokes beginning at age 4, may subtly distinguish this phenotype from classic HGPS.
In a patient with an apparently typical progeria phenotype (176670) who was 28 years old at the time that DNA was obtained, Cao and Hegele (2003) identified compound heterozygosity for 2 missense mutations in the LMNA gene. One mutation, arg471 to cys (R471C), resulted from a 1623C-T transition. An arg527-to-cys (R527C) substitution (150330.0026), resulting from a 1791C-T transition, was found on the other allele. These mutations were not identified in any of 100 control chromosomes. Parental DNA for this patient and a clinical description of the parents were not available. Brown (2004) reported that both he and the patient's physician, Francis Collins, concluded that the patient had mandibuloacral dysplasia (MADA; 248370).
Zirn et al. (2008) reported a 7-year-old Turkish girl, born of consanguineous parents, who was homozygous for the R471C mutation. She had a phenotype most consistent with an atypical form of MADA, including lipodystrophy, a progeroid appearance, and congenital muscular dystrophy with rigid spine syndrome. These latter features were reminiscent of Emery-Dreifuss muscular dystrophy (181350), although there was no cardiac involvement. She presented at age 10 months with proximal muscle weakness, contractures, spinal rigidity, and a dystrophic skeletal muscle biopsy. Characteristic progeroid features and features of lipodystrophy and mandibuloacral dysplasia were noted at age 3 years and became more apparent with age. Zirn et al. (2008) commented on the severity of the phenotype and emphasized the phenotypic variability in patients with LMNA mutations.
For discussion of the arg527-to-cys (R527C) mutation in the LMNA gene that was found in compound heterozygous state in a patient with mandibuloacral dysplasia (MADA; 248370) by Cao and Hegele (2003) and Brown (2004), see 150330.0025.
In a male patient whose phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, and hepatic steatosis (FPLD2; 151660), Caux et al. (2003) found a heterozygous 398G-T transversion in exon 2 of the LMNA gene that resulted in an arg-to-leu change at codon 133 (R133L) in the dimerization rod domain of lamins A and C. The patient also had hypertrophic cardiomyopathy with valvular involvement and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadened the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the possibility of hypertrophic cardiomyopathy and skin involvement.
Vigouroux et al. (2003) emphasized that a striking feature in the patient reported by Caux et al. (2003) was muscular hypertrophy of the limbs, which contrasts with the muscular atrophy usually present in Werner syndrome. Muscular hypertrophy, along with insulin-resistant diabetes and hypertriglyceridemia, is more often associated with LMNA-linked Dunnigan lipodystrophy. Fibroblasts from their patient showed nuclear abnormalities identical to those described in Dunnigan lipodystrophy (Vigouroux et al., 2001).
In 2 unrelated persons with a progeroid syndrome (see 176670), Chen et al. (2003) found heterozygosity for the R1333L mutation in the LMNA gene. One was a white Portuguese female who presented at the age of 9 years with short stature. She showed scleroderma-like skin changes and graying/thinning of hair. Type 2 diabetes developed at the age of 23 years. Hypogonadism, osteoporosis, and voice changes were also present. The other patient was an African American female in whom the diagnosis of a progeroid syndrome was made at the age of 18 years. Scleroderma-like skin, short stature, graying/thinning of hair, and type 2 diabetes at the age of 18 years were features. The deceased father, paternal aunt, and paternal grandmother of this patient were also diagnosed with severe insulin-resistant diabetes mellitus, suggesting that the R133L mutation might have been paternally inherited. It is noteworthy that a substitution in the same codon, R133P (150330.0032), was reported in a 40-year-old patient with Emery-Dreifuss muscular dystrophy who had disease onset at age 7 years and atrial fibrillation at age 32 years (Brown et al., 2001). Although Chen et al. (2003) designated these patients as having 'atypical Werner syndrome' (277700), Hegele (2003) suggested that the patients more likely had late-onset Hutchinson-Gilford progeria syndrome.
Jacob et al. (2005) studied the pattern of body fat distribution and metabolic abnormalities in the 2 patients with atypical Werner syndrome described by Chen et al. (2003). Patient 1, an African American female, had normal body fat (27%) by dual energy X-ray absorptiometry (DEXA). However, magnetic resonance imaging (MRI) revealed relative paucity of subcutaneous fat in the distal extremities, with preservation of subcutaneous truncal fat. She had impaired glucose tolerance and elevated postprandial serum insulin levels. In contrast, patient 2, a Caucasian female, had only 11.6% body fat as determined by DEXA and had generalized loss of subcutaneous and intraabdominal fat on MRI. She had hypertriglyceridemia and severe insulin-resistant diabetes requiring more than 200 U of insulin daily. Skin fibroblasts showed markedly abnormal nuclear morphology compared with those from patient 1. Despite the deranged nuclear morphology, the lamin A/C remained localized to the nuclear envelope, and the nuclear DNA remained within the nucleus. Jacob et al. (2005) concluded that atypical Werner syndrome associated with an R133L mutation in the LMNA gene is phenotypically heterogeneous. Furthermore, the severity of metabolic complications seemed to correlate with the extent of lipodystrophy.
Sebillon et al. (2003) described a family with a history of sudden cardiac death, congestive heart failure, and dilated cardiomyopathy (CMD1A; 115200). Five affected members had a heterozygous 481G-A transition in exon 2 of the LMNA gene, resulting in a glu161-to-lys (E161K) mutation. Dilated cardiomyopathy was present in only 2 patients, in whom onset of the disease was characterized by congestive heart failure and atrial fibrillation (at 29 and 44 years, respectively); heart transplantation was performed in both patients (at 34 and 51 years of age). In the 3 other affected members, the onset of disease was also characterized by atrial fibrillation at 22, 49, and 63 years, but without dilated cardiomyopathy. A 16-year-old male and 12-year-old female were also heterozygous for the mutation, but had no signs or symptoms of heart disease. The 5 affected members were a mother and 2 daughters in 1 branch of the family and 2 brothers in another branch. Two cardiac deaths were reported in the family history: sudden death at 38 years and congestive heart failure at 68 years. No significant atrioventricular block was observed in the family, except in 1 patient for whom cardiac pacing was necessary at 67 years of age because of sinoatrial block coexisting with atrial fibrillation. Sebillon et al. (2003) concluded that the phenotype in this family was characterized by early atrial fibrillation preceding or coexisting with dilated cardiomyopathy, without significant atrioventricular block, and without neuromuscular abnormalities.
Sebillon et al. (2003) described a family in which 5 patients with dilated cardiomyopathy with conduction defects (CMD1A; 115200) were heterozygous for a 1-bp insertion, 28insA, in exon 1 of the LMNA gene. Three additional patients were considered as phenotypically affected with documented dilated cardiomyopathy but were not available for DNA analysis. In the family history, there were 3 cardiac sudden deaths before 55 years of age. In the patients with dilated cardiomyopathy, 3 had associated atrioventricular block requiring pacemaker implantation, 1 had premature ventricular beats leading to a cardioverter defibrillator implantation, and 1 had a mild form of skeletal muscular dystrophy (mild weakness and wasting of quadriceps muscles, as well as myogenic abnormalities on electromyogram).
In an Iranian female with short stature and a progeroid syndrome (see 176670), Chen et al. (2003) found a heterozygous de novo ala57-to-pro substitution (A57P) resulting from a 584G-C transversion in the LMNA gene. Onset occurred in her early teens, and she was 23 years old at diagnosis. Hypogonadism, osteoporosis, osteosclerosis of digits, and dilated cardiomyopathy were described. Although Chen et al. (2003) designated this patient as having 'atypical Werner syndrome' (277700), Hegele (2003) suggested that the patient more likely had late-onset Hutchinson-Gilford progeria syndrome.
McPherson et al. (2009) suggested that the patient in whom Chen et al. (2003) identified an A57P LMNA mutation had a distinct phenotype involving dilated cardiomyopathy and hypergonadotropic hypogonadism (212112).
In a white Norwegian male with a progeroid syndrome (see 176670), Chen et al. (2003) found a leu140-to-arg (L140R) substitution resulting from an 834T-G transversion in the LMNA gene. The patient had onset at age 14 of cataracts, scleroderma-like skin, and graying/thinning of hair, as well as hypogonadism, osteoporosis, soft tissue calcification, and premature atherosclerosis. Aortic stenosis and insufficiency were also present. The patient died at the age of 36 years. Although Chen et al. (2003) designated this patient as having 'atypical Werner syndrome' (277700), Hegele (2003) suggested that the patient more likely had late-onset Hutchinson-Gilford progeria syndrome.
In a 40-year-old patient with Emery-Dreifuss muscular dystrophy (EDMD2; 181350) who had disease onset at age 7 years and atrial fibrillation at age 32 years, Brown et al. (2001) found an arg133-to-pro (R133P) mutation in the LMNA gene. Chen et al. (2003) noted that the same codon is involved in the arg133-to-leu (150330.0027) mutation in atypical Werner syndrome.
In 4 affected members of a consanguineous family from north India with features of mandibuloacral dysplasia with type A lipodystrophy (MADA; 248370). Plasilova et al. (2004) identified a homozygous 1626G-C transversion in exon 10 of the LMNA gene, resulting in a lys542-to-asn (K542N) substitution. The parents and 1 unaffected daughter were heterozygous for the mutation. Patients in this family showed uniform skeletal malformations such as acroosteolysis of the digits, micrognathia, and clavicular aplasia/hypoplasia, characteristic of mandibuloacral dysplasia. However, the patients also had classic features of Hutchinson-Gilford progeria syndrome (176670). Plasilova et al. (2004) suggested that autosomal recessive HGPS and MADA may represent a single disorder with varying degrees of severity.
In a young girl with congenital muscular dystrophy and progeroid features (see 613205), Kirschner et al. (2005) identified a 1824C-T transition in the LMNA gene, resulting in a de novo heterozygous missense mutation, ser143 to phe (S143F). The child presented during the first year of life with myopathy with marked axial weakness, feeding difficulties, poor head control and axial weakness. Progeroid features, including growth failure, sclerodermatous skin changes, and osteolytic lesions, developed later. At routine examination at age 8 years, she was found to have a mediolateral myocardial infarction.
In cultured skin fibroblasts derived from the patient reported by Kirschner et al. (2005), Kandert et al. (2007) found dysmorphic nuclei with blebs and lobulations that accumulated progressively with cell passage. Immunofluorescent staining showed altered lamin A/C organization and aggregate formation. There was aberrant localization of lamin-associated proteins, particularly emerin (EMD; 300384) and nesprin-2 (SYNE2; 608442), which was reduced or absent from the nuclear envelope. However, a subset of mutant cells expressing the giant 800-kD isoform of SYNE2 showed a milder phenotype, suggesting that this isoform exerts a protective effect. Proliferating cells were observed to express the 800-kD SYNE2 isoform, whereas nonproliferating cells did not. In addition, mutant cells showed defects in the intranuclear organization of acetylated histones and RNA polymerase II compared to control cells. The findings indicated that the S143F mutant protein affects nuclear envelope architecture and composition, chromatin organization, gene expression, and transcription. The findings also implicated nesprin-2 as a structural reinforcer at the nuclear envelope.
In 9 affected members of Dutch family diagnosed with limb-girdle muscular dystrophy type 1B (LGMD1B), which was later reclassified as Emery-Dreifuss muscular dystrophy (EDMD2; 181350) by Straub et al. (2018), van Engelen et al. (2005) identified a 777T-A transversion in the LMNA gene, resulting in a tyr259-to-ter substitution (Y259X). The heterozygous Y259X mutation led to a classic LGMD1B phenotype. One infant homozygous for the mutation was born of consanguineous parents who were both affected, and delivered at 30 weeks' gestational age by cesarean section because of decreasing cardiac rhythm. The infant died at birth from very severe generalized muscular dystrophy. Cultured skin fibroblasts from the infant showed complete absence of A-type lamins leading to disorganization of the lamina, alterations in the protein composition of the inner nuclear membrane, and decreased life span. Van Engelen et al. (2005) noted that the fibroblasts from this child showed remarkable similarity, in nuclear architectural defects and in decreased life span, to the fibroblasts of homozygous LMNA (L530P/L530P) mice (Mounkes et al., 2003).
Restrictive Dermopathy 2
In a premature infant (P1) who died at 6 months of age due to restrictive dermopathy (RSDM2; 619793), Navarro et al. (2004) identified a heterozygous G-to-A transition at position 1 in the intron 11 donor site of the LMNA gene (IVS11+1G-A), resulting in loss of exon 11 from the transcript. The patient expressed lamins A and C and a truncated prelamin A. Patient cells showed an abnormal transcript with an in-frame deletion of the entire exon 11 (270 bp), predicted to cause an internal deletion of 90 residues corresponding to a large part of the globular domain (Gly567_Gln656del).
Barthelemy et al. (2015) analyzed LMNA exon 11 transcripts in cells derived from the patient reported by Navarro et al. (2004). In addition to production of a normal full-length prelamin A transcript, there was a band corresponding to prelamin A(del50) (progerin), and an additional transcript correlation to prelamin A(del90) resulting from the skipping of all of exon 11. The prelamin A(del90) transcript was termed 'dermopathin.'
Hutchinson-Guilford Progeria Syndrome
In a patient with an extremely severe form of Hutchinson-Guilford progeria syndrome (HGPS; 176670), Moulson et al. (2007) identified a heterozygous G-to-A transition at the +1 position of the donor splice site of intron 11 in the LMNA gene (1968+1G-A). RT-PCR studies showed a truncated protein product identical to that observed in HGPS cell lines with the common 1824C-T mutation (150330.0022), indicating that the new mutation resulted in the abnormal use of the same cryptic exon 11 splice site. The findings were in contrast to those reported by Navarro et al. (2004), who observed skipping of exon 11 with 1968+1G-A. Further quantitative studies of the patient's cells by Moulson et al. (2007) found a 4.5-fold increase in the relative ratio of mutant mRNA and protein to wildtype prelamin A compared to typical HGPS cells. The findings were confirmed by Western blot analysis and provided an explanation for the severe phenotype observed in this patient. He had had abnormally thick and tight skin observed at 11 weeks of age, and developed more typical but severe progeroid features over time. He died of infection at age 3.5 years.
In 2 unrelated Turkish patients with mandibuloacral dysplasia with type A lipodystrophy (MADA; 248370), a 21-year-old woman previously described by Cogulu et al. (2003) and an 18-year-old man, Garg et al. (2005) identified homozygosity for a 1586C-T transition in the LMNA gene, resulting in an ala529-to-val (A529V) substitution. Intragenic SNPs revealed a common haplotype spanning 2.5 kb around the mutated nucleotide in the parents of both patients, suggesting ancestral origin of the mutation. The female patient had no breast development despite normal menstruation, a phenotype different from that seen in women with the R527H mutation (150330.0021).
In a German woman diagnosed with limb-girdle muscular dystrophy type 1B (LGMD1B), which was reclassified as Emery-Dreifuss muscular dystrophy by Straub et al. (2018), Rudnik-Schoneborn et al. (2007) identified a heterozygous 1477C-T transition in exon 8 of the LMNA gene, resulting in a gln493-to-ter (Q493X) substitution. She presented with slowly progressive proximal muscle weakness beginning in the lower extremities and later involving the upper extremities. EMG showed both neurogenic and myopathic defects in the quadriceps muscle. At age 53 years, she was diagnosed with atrioventricular conduction block and arrhythmia requiring pacemaker implantation. Family history showed that her mother had walking difficulties from age 40 years and died of a heart attack at age 54. Six other deceased family members had suspected cardiomyopathy without muscle involvement.
Morel et al. (2006) reported 2 sisters, the children of nonconsanguineous Punjabi parents, with familial partial lipodystrophy type 2 (FPLD2; 151660). The first presented with acanthosis nigricans at age 5 years, diabetes with insulin resistance, hypertension, and hypertriglyceridemia at age 13 years, and partial lipodystrophy starting at puberty. Her sister and their mother had a similar metabolic profile and physical features, and their mother died of vascular disease at age 32 years. LMNA sequencing showed that the sisters were each heterozygous for a novel G-to-C mutation at the intron 8 consensus splice donor site, which was absent from the genomes of 300 healthy individuals. The retention of intron 8 in mRNA predicted a prematurely terminated lamin A isoform (516 instead of 664 amino acids) with 20 nonsense 3-prime terminal residues. The authors concluded that this was the first LMNA splicing mutation to be associated with FPLD2, and that it causes a severe clinical and metabolic phenotype.
In a patient with a severe form of Hutchinson-Gilford progeria syndrome (HGPS; 176670), Moulson et al. (2007) identified a de novo heterozygous 1821G-A transition in exon 11 of the LMNA gene, resulting in a val607-to-val (V607V) substitution. The 1821G-A mutation favored the use of the same cryptic splice site as the common 1824C-T mutation (150330.0022) and produced the same resultant progerin product. However, the ratio of mutant to wildtype mRNA and protein was increased in the patient compared to typical HGPS cells. The patient had flexion contractures, thick and tight skin, and other severe progeroid features. He died of infection at 26 days of age.
In a 50-year-old Italian woman with sporadic dilated cardiomyopathy with conduction defects (CMD1A; 115200), Taylor et al. (2003) identified heterozygosity for a 1718C-T transition in exon 11 of the LMNA gene, resulting in a ser573-to-leu substitution at a highly conserved residue, predicted to affect the carboxyl tail of the lamin A isoform. The mutation was not found in the proband's 2 unaffected offspring or in 300 control chromosomes, but her unaffected 60-year-old sister also carried the mutation.
Van Esch et al. (2006) analyzed the LMNA gene in a 44-year-old male of European descent with arthropathy, tendinous calcifications, and a progeroid appearance (see 248370) and identified homozygosity for the S573L mutation. Progeroid features included a small pinched nose, small lips, micrognathia with crowded teeth, cataract, and alopecia. He also had generalized lipodystrophy, and sclerodermatous skin. The arthropathy affected predominantly the distal femora and proximal tibia in the knee with tendinous calcifications. However, he had normal clavicles and no evidence of acroosteolysis. The authors concluded that he had a novel phenotype. The patient's unaffected 15-year-old son was heterozygous for the mutation, which was not found in 450 control chromosomes. The authors noted that the patient had no evidence of cardiomyopathy and his 70-year-old mother, an obligate heterozygote, had no known cardiac problems.
In a 75-year-old European male with partial lipodystrophy (FPLD2; 151660), Lanktree et al. (2007) identified heterozygosity for the S573L mutation in the LMNA gene.
In a 46-year-old South Asian female with partial lipodystrophy (FPLD2; 151660), Lanktree et al. (2007) identified heterozygosity for a 688G-A transition in exon 4 of the LMNA gene, resulting in an asp230-to-asn (D230N) substitution at a conserved residue located 5-prime to the nuclear localization signal. The mutation, predicted to affect only the lamin A isoform, was not found in 200 controls of multiple ethnic backgrounds.
In a 50-year-old European female with partial lipodystrophy (FPLD2; 151660), Lanktree et al. (2007) identified heterozygosity for a 1195C-T transition in exon 7 of the LMNA gene, resulting in an arg399-to-cys (R399C) substitution at a conserved residue located 5-prime to the nuclear localization signal. The mutation, predicted to affect only the lamin A isoform, was not found in 200 controls of multiple ethnic backgrounds.
Decaudain et al. (2007) identified a heterozygous R399 mutation in a woman with severe metabolic syndrome. She was diagnosed with insulin-resistant diabetes at age 32. Chronic hyperglycemia led to retinopathy, peripheral neuropathy, and renal failure. She had severe hypertriglyceridemia and diffuse atherosclerosis, requiring coronary artery bypass at age 49. Physical examination revealed android fat distribution with lipoatrophy of lower limbs and calves hypertrophy without any muscle weakness. Her mother and a brother had diabetes and died several years earlier.
In a 27-year-old Italian woman with a mandibuloacral dysplasia type A (MADA; 248370)-like phenotype, Lombardi et al. (2007) found compound heterozygosity for missense mutations in the LMNA cDNA: a G-to-A transition at position 1318 in exon 7 that gave rise to a val-to-met substitution at codon 440 (V440M), and an R527H substitution (150330.0021). Each healthy parent was a simple heterozygote for one or the other mutation. The apparent MADA phenotype was associated with muscular hyposthenia and generalized hypotonia. Clavicular hypoplasia and metabolic imbalances were absent. Lombardi et al. (2007) hypothesized that lack of homozygosity for the R527H mutation attenuated the MADA phenotype, while the V440M mutation may have contributed to both the muscle phenotype and the pathogenic effect of the single R527H mutation.
In affected members of a Slovenian family with heart-hand syndrome (610140), originally reported by Sinkovec et al. (2005), Renou et al. (2008) identified heterozygosity for a T-G transversion in intron 9 of the LMNA gene (IVS9-12T-G), predicted to cause a frameshift and premature termination in exon 10, with the addition of 14 new amino acids at the C terminus. The mutation was not found in unaffected family members or in 100 healthy controls. Analysis of fibroblasts from 2 affected individuals confirmed the presence of truncated protein and revealed aberrant localization of lamin A/C accumulated in intranuclear foci as well as dysmorphic nuclei with nuclear envelope herniations.
In a 56-year-old Japanese woman, born of consanguineous parents, with mandibuloacral dysplasia and type A lipodystrophy (MADA; 248370), Kosho et al. (2007) identified a homozygous 1585G-A transition in exon 9 of the LMNA gene, resulting in an ala529-to-thr (A529T) substitution. The authors stated that she was the oldest reported patient with the disorder. In addition to classic MAD with lipodystrophy type A phenotype, including progeroid appearance, acroosteolysis of the distal phalanges, and loss of subcutaneous fat in the limbs, she had severe progressive destructive skeletal and osteoporotic changes. Vertebral collapse led to paralysis. However, Kosho et al. (2007) also noted that other factors may have contributed to the severe osteoporosis observed in this patient. Another mutation in this codon, A529V (150330.0037), results in a similar phenotype.
In a 7-year-old boy with a LMNA-related congenital muscular dystrophy (613205), Quijano-Roy et al. (2008) identified a de novo heterozygous mutation in exon 6 of the LMNA gene, resulting in a leu380-to-ser (L380S) substitution. He showed decreased movements in utero, hypotonia, talipes foot deformities, no head or trunk control, distal joint contractures, respiratory insufficiency, and paroxysmal atrial tachycardia. Serum creatine kinase was increased, and muscle biopsy showed dystrophic changes.
In a 9-year-old girl with congenital muscular dystrophy (613205), Quijano-Roy et al. (2008) identified a de novo heterozygous mutation in exon 4 of the LMNA gene, resulting in an arg249-to-trp (R249W) substitution. She presented at age 3 to 6 months with axial weakness and talipes foot deformities. She lost head support at 9 months, had respiratory insufficiency, joint contractures, and axial and limb muscle weakness. A de novo heterozygous R249W mutation was also identified in an unrelated 3-year-old boy with congenital LGMD1B who showed decreased movements in utero, hypotonia, distal contractures, no head or trunk control, and respiratory insufficiency. Both patients had increased serum creatine kinase and showed myopathic changes on EMG studies.
Scharner et al. (2011) found that transfection of the R249W mutation into cells resulted in increased expression of mutant LMNA, mislocalization of the protein in the nucleus, abnormal nuclear morphology with lobules, and mislocalization of lamin B (LMNB; 150340).
Mercuri et al. (2004) identified a de novo heterozygous 1072G-A transition in exon 5 of the LMNA gene, resulting in a glu358-to-lys (E358K) substitution, in 5 unrelated patients with muscular dystrophy. Three patients had the common phenotype of autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; 181350), 1 was diagnosed with early-onset limb-girdle muscular dystrophy type 1B (LGMD1B), which was reclassified as EDMD2 by Straub et al. (2018), and the last had had a more severe disorder consistent with congenital muscular dystrophy (613205). The mutation was not identified in 150 controls. The patient with LGMD1B also had cardiac conduction abnormalities, respiratory failure, and features of lipodystrophy (FPLD2; 151660). Mercuri et al. (2004) commented on the extreme phenotypic variability associated with this mutation.
In 4 unrelated patients with LMNA-related congenital muscular dystrophy, Quijano-Roy et al. (2008) identified a de novo heterozygous mutation in exon 6 of the LMNA gene, resulting in a glu358-to-lys (E358K) substitution. Three patients presented before 1 year of age with hypotonia and later developed head drop with neck muscle weakness. There was delayed motor development with early loss of ambulation, distal limb contractures, axial and limb muscle weakness, respiratory insufficiency requiring mechanical ventilation, increased serum creatine kinase, and dystrophic changes on muscle biopsy. One patient developed ventricular tachycardia at age 20 years. The fourth patient with congenital LGMD1B had decreased fetal movements and presented at age 3 to 6 months with hypotonia, loss of head control, and delayed motor development.
In an 18-month-old boy with LMNA-related congenital muscular dystrophy (613205), D'Amico et al. (2005) identified a de novo heterozygous 3-bp deletion (94delAAG) in exon 1 of the LMNA gene, resulting in the deletion of lys32. Although he had normal early motor development, he showed prominent neck extensor weakness resulting in a 'dropped head' phenotype at age 1 year. He was able to stand independently but had some difficulty walking.
This variant is classified as a variant of unknown significance because its contribution to various phenotypes has not been confirmed.
An arg644-to-cys (R644C) mutation in the LMNA gene has been found in several different phenotypic presentations (Genschel et al., 2001; Mercuri et al., 2005; Rankin et al., 2008), but the pathogenicity of the mutation has not been confirmed (Moller et al., 2009).
In a German patient with dilated cardiomyopathy with no history of conduction system disease (see 115200), Genschel et al. (2001) identified heterozygosity for a 1930C-T transition in exon 11 of the LMNA gene resulting in an R644C substitution in the C-terminal domain of lamin A. The authors noted that the mutation is solely within lamin A, but not lamin C, whereas previously reported mutations causing dilated cardiomyopathy are located more in the rod domain of the protein.
Mercuri et al. (2005) identified heterozygosity for the R644C mutation in 4 patients with skeletal and cardiac muscle involvement of varying severity. In 1 patient, the mutation was found in the affected brother and the unaffected father, and was not found in the affected mother. The mutation was not found in 100 unrelated control subjects.
Rankin et al. (2008) described 9 patients in 8 families with the R644C mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance; patient 1 also had focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular noncompaction, patient 5 with severe scoliosis and contractures, patient 6 with limb-girdle weakness, and patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 were brothers who had proximal weakness and contractures. The same mutation was identified in 9 unaffected individuals in these 9 families, but was not detected in 200 German and 300 British controls. Rankin et al. (2008) suggested that extreme phenotypic diversity and low penetrance are associated with the R644C mutation.
In a 17-year-old Caucasian female with dilated cardiomyopathy and ovarian failure (212112), Nguyen et al. (2007) identified heterozygosity for a de novo 176T-C transition in exon 1 of the LMNA gene, predicted to result in a leu59-to-arg (L59R) substitution. Analysis of nuclear morphology in patient fibroblasts showed more irregularity and variation than that of control fibroblasts, with denting, blebbing, and irregular margins. The mutation was not found in the unaffected parents or in 116 population-based controls.
In a 15-year-old Caucasian girl with dilated cardiomyopathy and ovarian failure who died from an arrhythmia while awaiting cardiac transplantation, McPherson et al. (2009) identified heterozygosity for the L59R mutation in the LMNA gene. The mutation was presumed to be de novo, although the unaffected parents declined DNA testing. The patient also had a healthy older sister, and there was no family history of cardiomyopathy or hypogonadism.
In 2 sibs with dilated cardiomyopathy (CMD1A; 115200), Malek et al. (2011) identified a heterozygous 1621C-G transversion in exon 10 of the LMNA gene, resulting in an arg541-to-gly (R541G) substitution in the C-terminal tail region. The 23-year-old male proband had a history of paroxysmal atrioventricular nodal reentrant tachycardia and was found by echocardiogram to have dilation of the left ventricle and global hypokinesis. Cardiac MRI showed discrete regional areas of akinesis with muscle thinning in the left ventricle and marked hypertrabeculation in dysfunctional regions, as well as evidence of fibrosis. The proband's sister had sinus bradycardia and supraventricular and ventricular arrhythmias, but normal echocardiogram and cardiac MRI. The sibs' father and paternal aunt had both died of dilated cardiomyopathy. In vitro functional expression studies showed that the R541G mutant resulted in the formation of abnormal lamin aggregates, most of which were sickle-shaped, suggesting aberrant formation of the inner nuclear lamina from misassembled lamin dimers.
In 4 sibs, born of consanguineous Spanish parents, with autosomal recessive Emery-Dreifuss muscular dystrophy-3 (EDMD3; 616516), Jimenez-Escrig et al. (2012) identified a homozygous c.674G-A transition in exon 4 of the LMNA gene, resulting in an arg225-to-gln (R225Q) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in 200 control chromosomes. Functional studies of the variant were not performed.
In 2 sibs and a mother with a protracted form of Hutchinson-Gilford progeria syndrome (HGPS; 176670), Hisama et al. (2011) identified a heterozygous c.1968G-A transition at the last nucleotide of exon 11 of the LMNA gene, predicted to result in a nonsynonymous gln656-to-gln (Q656Q) substitution. However, analysis of patient cells showed that the mutation affected splicing, resulting in an in-frame deletion of 150 nucleotides that corresponded to progerin (see 150330.0022) observed in patients with HGPS. The ratio of progerin/lamin A was 0.15, which is one-quarter that observed in HGPS cells. The patients had adult-onset severe coronary artery disease and a progeroid appearance.
Barthelemy et al. (2015) identified a heterozygous c.1968G-A (c.1968G-A, NM_1707073) transition in the LMNA gene in another patient with adult-onset HGPS manifest as progeroid features and severe atherosclerosis necessitating bypass surgery at age 35. Analysis of LMNA exon 11 transcripts in patient cells showed the production of a normal full-length prelamin A transcript, a band corresponding to prelamin A(del50) (progerin), and an additional transcript corresponding to prelamin A(del90) resulting from the skipping of all of exon 11. Barthelemy et al. (2015) termed the prelamin A(del90) transcript 'dermopathin' because it was first observed in a patient with restrictive dermopathy (275210) by Navarro et al. (2004) (see 150330.0036). Dermopathin excludes the 270 nucleotides of exon 11 and is predicted to cause an internal deletion preserving the prelamin A open reading frame (Gly567_Gln656del). In fibroblasts derived from 2 of the patients reported by Hisama et al. (2011), Barthelemy et al. (2015) presented preliminary evidence that a polymorphism in exon 10 of the LMNA gene (rs4641) may influence the production of various transcripts.
In a woman with a protracted form of Hutchinson-Gilford progeria syndrome (HGPS; 176670) manifest as severe coronary artery disease and progeroid features, Hisama et al. (2011) identified a heterozygous G-to-A transition (c.1968+5G-A) in the donor splice site of intron 11 of the LMNA gene, resulting in a 150-bp deletion. Western blot analysis of patient cells showed progerin at lower levels than in classic HGPS patient cells.
Barthelemy et al. (2015) identified a heterozygous c.1968+5G-A transition (c.1968+5G-A, NM_170707.3) in the LMNA gene in another patient with atypical HGPS manifest as progeroid features and cardiac disease. He died at age 17 years of hypertrophic cardiomyopathy and aortic and mitral valve stenosis. Analysis of LMNA exon 11 transcripts in patient cells showed the production of a normal full-length prelamin A transcript, a band corresponding to prelamin A(del50) (progerin), and an additional transcript correlating to prelamin A(del90) resulting from the skipping of all of exon 11. Barthelemy et al. (2015) termed the prelamin A(del90) transcript 'dermopathin' because it was first observed in a patient with restrictive dermopathy (275210) by Navarro et al. (2004) (see 150330.0036). Dermopathin excludes the 270 nucleotides of exon 11 and is predicted to cause an internal deletion preserving the prelamin A open reading frame (Gly567_Gln656del).
In affected members of a family with a protracted form of Hutchinson-Gilford progeria syndrome (HGPS; 176670) manifest as premature cutaneous and cardiac aging, Kane et al. (2013) identified a heterozygous c.899A-G transition in the LMNA gene, resulting in an asp300-to-gly (D300G) substitution at a highly conserved residue in the second coiled-coil domain. The mutation, which segregated with the disorder in the family, was not found in the 1000 Genomes Project (Phase 1) or Exome Variant Server databases or in 100 control chromosomes. The affected domain mediates lamin protein dimerization and promotes filament formation. Skin fibroblasts derived from the proband showed abnormal morphology, including blebs, lobulation, and ringed or donut-shaped nuclei. Although the processing of lamin A and C were normal in patient cells, treatment with farnesyltransferase inhibitors resulted in improved nuclear morphology. Overexpression of the mutation in control fibroblasts led to abnormal nuclear morphology in a dominant-negative manner.
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