Alternative titles; symbols
HGNC Approved Gene Symbol: LBR
SNOMEDCT: 1237412001, 389261002, 715401008, 85559002;
Cytogenetic location: 1q42.12 Genomic coordinates (GRCh38): 1:225,401,502-225,428,821 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q42.12 | ?Reynolds syndrome | 613471 | Autosomal dominant | 3 |
| Greenberg skeletal dysplasia | 215140 | Autosomal recessive | 3 | |
| Pelger-Huet anomaly | 169400 | Autosomal dominant | 3 | |
| Rhizomelic skeletal dysplasia with or without Pelger-Huet anomaly | 618019 | Autosomal recessive | 3 |
The LBR gene encodes the lamin B receptor, an inner nuclear membrane protein that binds lamin B (LMNB1; 150340 and LMNB2; 150341). The nuclear envelope is composed of the nuclear lamina, the nuclear pore complexes, and the nuclear membranes. The nuclear membranes can be divided into 3 morphologically distinct but interconnected domains: the outer nuclear membrane, the inner nuclear membrane, and the nuclear pore membrane. The inner nuclear membrane is adjacent to the nuclear lamina, a meshwork of intermediate filament proteins termed lamins. The nuclear lamina is a discontinuous structure that occupies only a fraction of the nuclear periphery, and at some points, the inner nuclear membrane may interact directly with the chromatin. Several integral proteins of the nuclear envelope inner membrane that may be associated with the lamina and the chromatin have been identified (summary by Ye and Worman, 1994).
Ye and Worman (1994) isolated clones corresponding to the LBR gene from a HeLa cell cDNA library. The deduced 615-residue protein showed 68% amino acid identity with the chicken lamin B receptor. The LBR protein has a basic nucleoplasmic N-terminal domain of 208 amino acids followed by a hydrophobic domain with 8 putative transmembrane segments. Phosphorylation sites were also identified. The LBR N-terminal domain precipitated lamin B from nuclear extracts and associated with DNA. The stretch between amino acids 71 and 100, which contains a ser/arg-rich stretch, was necessary for DNA binding. The findings suggested that LBR can potentially mediate the interaction of both the nuclear lamina and the chromatin with the inner nuclear membrane.
Worman et al. (1988) cloned avian lamin B receptor (LBR) that binds in vitro to lamin B. Subsequently, Courvalin et al. (1990) identified a mammalian homolog of avian LBR was identified by cross-reactive autoantibodies from patients with primary biliary cirrhosis.
In fibroblasts and HeLa cells, Clayton et al. (2010) found localization of LBR outside of the nuclear membrane, where it colocalized with markers of the endoplasmic reticulum. LBR was also expressed in lymphoblastoid cells, differentiated osteoclasts, and osteosarcoma cells. Developing mouse embryos showed strong Lbr expression in the liver, lung, midgut, skin, brain, and developing cartilage. Lbr was also detected in growth plate cartilage, osteoblasts, and connective tissue fibroblasts.
Schuler et al. (1994) showed by restriction mapping that the human LBR transcription unit spans approximately 35 kb. A transcription start site is located approximately 4 kb 5-prime to the translation initiation codon. The LBR gene contains 13 protein-coding exons. The nucleoplasmic domain is encoded by exons 1 to 4, and the hydrophobic domain, with 8 putative transmembrane segments, is encoded by exons 5 to 13. The hydrophobic domain is homologous to 3 yeast polypeptides, suggesting that this higher eukaryotic gene may have evolved through recombination between a gene that encoded a soluble nuclear protein and a membrane protein gene similar to those in yeast.
Wydner et al. (1996) mapped the LBR gene to chromosome 1q42.1 by fluorescence in situ hybridization.
Differentiation of olfactory sensory neurons is characterized by expression of a single olfactory receptor. Clowney et al. (2012) found that silenced olfactory receptor genes from different chromosomes converged into approximately 5 distinct foci within nuclei of mouse olfactory sensory neurons. The active olfactory receptor gene was absent from these foci. Clowney et al. (2012) found that loss of Lbr expression was critical for chromatin compaction and silencing of olfactory receptor genes. Expression of Lbr in mouse olfactory sensory neurons caused redistribution of olfactory receptor gene foci to the nuclear envelope, concomitant with loss of specific olfactory receptor gene expression by individual neurons. Lbr expression did not alter expression of nonolfactory receptor genes and did not alter the distribution of primary heterochromatin marks. Clowney et al. (2012) concluded that the primary epigenetic signature silencing olfactory receptor genes is reinforced by secondary and tertiary repressive organization and that absence of LBR is required for formation of the necessary higher-order repressive heterochromatin.
Pelger-Huet Anomaly
Pelger-Huet anomaly (169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy, and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies, and increased pre- and postnatal mortality in association with Pelger-Huet anomaly (Nachtsheim, 1950). By genomewide linkage scan, Hoffmann et al. (2002) showed that Pelger-Huet anomaly is linked to 1q41-q43. In the LBR gene, which resides in this region, they identified 4 splice site, 2 frameshift, and 2 nonsense mutations. The lamin B receptor, a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Hoffmann et al. (2002) found that lymphoblastoid cells from heterozygous individuals affected with Pelger-Huet anomaly showed reduced expression of the lamin B receptor, and cells homozygous with respect to Pelger-Huet anomaly contain only trace amounts of it. They found that expression of the lamin B receptor affected neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Since the lamin B receptor may be a sterol reductase, loss of most LBR expression might lead to changes in sterol metabolism that cause developmental abnormalities, as has been shown for the highly homologous delta-7 sterol reductase (DHCR7; 602858), which is mutant in Smith-Lemli-Opitz syndrome (270400).
Following linkage studies in 2 families with Pelger-Huet anomaly, Best et al. (2003) sequenced the LBR gene and identified 2 mutations present in heterozygous state (600024.0004-600024.0005). In addition, the LBR gene was sequenced in a single English man with Pelger-Huet anomaly and a third mutation was identified (600024.0006).
Greenberg Dysplasia
Greenberg dysplasia (GRBGD; 215140), also known as hydrops-ectopic calcification-moth-eaten (HEM) skeletal dysplasia, is an autosomal recessive chondrodystrophy with a lethal course, characterized by fetal hydrops, short limbs, and abnormal chondroosseous calcification. Waterham et al. (2003) found elevated levels of cholesta-8,14-dien-3-beta-ol in cultured skin fibroblasts of an 18-week-old fetus with HEM skeletal dysplasia, compatible with a deficiency of the cholesterol biosynthetic enzyme 3-beta-hydroxysterol delta(14)-reductase. Sequence analysis of 2 candidate genes encoding putative human 3-beta-hydroxysterol delta(14)-reductases, TM7SF2 (603414) and LBR, identified a mutation in the LBR gene that resulted in a truncated protein (600024.0003). The healthy mother showed hypolobulated nuclei in 60% of her granulocytes. Waterham et al. (2003) thus suggested that classic Pelger-Huet anomaly represents the heterozygous state of 3-beta-hydroxysterol delta(14)-reductase deficiency. Waterham et al. (2003) stated that HEM skeletal dysplasia was the sixth inherited disorder of cholesterol biosynthesis for which the molecular basis was resolved. An abnormal granulocyte chromatin structure occurs in heterozygous and homozygous individuals with Pelger-Huet anomaly and severe skeletal abnormalities occur in individuals with homozygous HEM skeletal dysplasia, which indicates that the lamin B receptor has 2 different physiologic functions: preserving chromatin structure by promoting heterochromatin binding to the inner nuclear membrane (Ye and Worman, 1994) and functioning as the primary sterol delta(14)-reductase in human cholesterol biosynthesis. Waterham et al. (2003) stated that the latter function was somewhat unexpected, as all enzymes involved in the postsqualene cholesterol biosynthesis pathway had been localized to the ER membrane, whereas the lamin B receptor is present (at least predominantly) in the inner nuclear membrane. In this respect, the gene product of TM7SF2 seemed a priori a better candidate because it is localized in the ER membrane and also exhibits sterol delta(14)-reductase activity.
Wassif et al. (2007) studied mice with deficits of Lbr and/or Tm7sf2, another sterol delta(14)-reductase, and demonstrated that these proteins provide substantial enzymatic redundancy with respect to cholesterol synthesis; they concluded, therefore, that HEM dysplasia is a laminopathy rather than an inborn error of cholesterol synthesis.
In 3 unrelated fetuses with Greenberg dysplasia, Clayton et al. (2010) identified homozygous or compound heterozygous mutations in the LBR gene (600024.0008-600024.0011). A parent who was heterozygous for a missense mutation in the sterol reductase domain had no abnormalities of peripheral blood cells, whereas this missense mutation was shown to result in a loss of sterol reductase activity. Cellular studies showed localization of LBR outside of the nuclear membrane, where it colocalized with markers of the endoplasmic reticulum. Nonnuclear LBR was also expressed in lymphoblastoid cells, differentiated osteoclasts, and osteosarcoma cells, as well as in various tissues of developing mouse embryos. These findings suggested to Clayton et al. (2010) that Greenberg dysplasia results from defects in the sterol reductase activity of LBR, not from the structural function of LBR as part of the nuclear membrane. The uncoupling of the metabolic and structural functions of LBR explained how mutations in the same gene can cause distinct disorders. The findings also indicated that sterol reductase function is essential for intrauterine development in humans.
In a fetus with Greenberg dysplasia who had a presumed diagnosis of achondrogenesis-1A (200600), Wehrle et al. (2018) performed Sanger sequencing of the TRIP11 gene (604505) and did not demonstrate molecular confirmation of the clinical and radiographic diagnosis. They then performed whole-exome sequencing and identified a novel homozygous splice site mutation in the LBR gene (600024.0019). The mutation, which was confirmed by Sanger sequencing, was found in heterozygous state in the unaffected parents. LBR mRNA in patient-derived fibroblasts was barely detectable by real-time PCR, compatible with nonsense-mediated decay. Western blot analysis and immunofluorescence demonstrated that the fetal cells were completely devoid of LBR protein.
By whole-exome sequencing in 2 sib fetuses with Greenberg dysplasia, Giorgio et al. (2019) identified a homozygous missense mutation in the LBR gene (D460R; 600024.0020). The parents were heterozygous for the mutation.
Rhizomelic Skeletal Dysplasia with or without Pelger-Huet Anomaly
By sequence analysis of the LBR gene in an adopted 12-year-old girl with rhizomelic skeletal dysplasia with Pelger-Huet anomaly (SKPHA; 618019), Borovik et al. (2013) identified compound heterozygosity for 2 mutations (600024.0012-600024.0013).
Sobreira et al. (2014) identified compound heterozygous mutations (R76X, 600024.0014 and N547S, 600024.0015) in the LBR gene in a 15-year-old boy with mild skeletal anomalies and PHA. The N547S mutation was present in heterozygosity in the mother and unaffected brothers of the proband, and neither mutation was identified in the father. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing.
By exome sequencing in 2 unrelated patients with short stature, spondylometaphyseal dysplasia, and spontaneously improving rhizomelic limb shortening, Thompson et al. (2019) identified compound heterozygous and homozygous mutations in the LBR gene (see, e.g., R502G, 600024.0016 and R583L, 600024.0017). Pelger-Huet anomaly was present in patient 1 but was not ascertained in patient 2.
Using a gene panel targeting skeletal disorders, Collins et al. (2020) identified a homozygous missense mutation in the LBR gene (L456V; 600024.0018) in 2 middle-aged sisters with short stature with predominant rhizomelia of the upper limbs and mesomelia of the lower limbs without Pelger-Huet anomaly. Homozygosity was confirmed in patient 2 by Sanger sequencing.
Reynolds Syndrome
In a 76-year-old Caucasian woman with Reynolds syndrome (613471), comprising primary biliary sclerosis, scleroderma, Raynaud phenomenon, and telangiectasia, Gaudy-Marqueste et al. (2010) identified a heterozygous mutation in the LBR gene (R372C; 600024.0007). Blood smear did not show Pelger-Huet anomaly. Studies of patient lymphoblastoid cells did not show abnormalities, but patient fibroblasts showed decreased LBR and decreased levels of lamin proteins, as well as dysmorphic nuclei with mottled chromatin. These findings suggested that the R372C mutation exerted a dominant-negative effect on LBR-interacting proteins, perhaps resulting from decreased stabilization of the mutant protein and increased proteosome-mediated degradation.
In 2 independent mouse strains with an associated Pelger-Huet anomaly blood phenotype (Green et al., 1975), Hoffmann et al. (2002) found 1 frameshift and 1 nonsense mutation in the Lbr gene.
Mice with the 'ichthyosis' (ic) phenotype display marked abnormalities in nuclear heterochromatin, similar to those observed in Pelger-Huet anomaly (PHA). Shultz et al. (2003) observed that mice homozygous for deleterious mutations at the ic locus present with a blood phenotype similar to PHA and develop other phenotypic abnormalities, including alopecia, variable expression of syndactyly, and hydrocephalus. The ic locus on mouse chromosome 1 shares conserved synteny with the chromosomal location of the human LBR locus on human chromosome 1. Shultz et al. (2003) identified 1 nonsense and 2 frameshift mutations within the Lbr gene of mice homozygous for 1 of 3 independent mutations (ic, icJ, or ic4J, respectively) at the ichthyosis locus. These allelic mutations resulted in a truncated or severely impaired protein. Tissues from mice homozygous for the icJ mutation revealed a complete loss of Lbr protein, as shown by immunofluorescence microscopy and immunoblotting.
Using a gene-trap (GT) method, Cohen et al. (2008) created mice homozygous for an insertion into exon 9 of the Lbr gene (Lbr GT/GT mice), resulting in a C-terminally truncated protein. Lbr GT/GT mice exhibited embryonic lethality with incomplete penetrance, shortened postnatal life span, hydrocephaly, and syndactyly, as well as chromatin atypia in neutrophils. Lbr GT/GT fibroblasts had wrinkled nuclei or smooth nuclei associated with micronuclei, as well as mislocalized nuclear proteins. Granulocyte number was enhanced in Lbr GT/GT mice, and mutant granulocytes lacked mature segmented nuclei, with a block in late maturation. However, mutant granulocytes showed normal ability to kill bacteria.
Pelger-Huet Anomaly
Pelger-Huet anomaly (PHA; 169400) is unusually frequent in the mountain village of Gelenau in southeastern Germany (Karl, 1967). To identify the genetic cause of Pelger-Huet anomaly, Hoffmann et al. (2002) studied 11 families from Gelenau with 18 unaffected and 29 affected members. In all of the families, neutrophils of affected individuals had bilobed or rod-like nuclei. Hoffmann et al. (2002) identified 3 related haplotypes associated with PHA, which indicated the presence of a founder haplotype in 10 of the 11 families. Although ancestral recombination events had eroded this founder haplotype, 10 families shared a crucial region defined by 2 particular markers. All 10 families sharing the founder haplotype were found by Hoffmann et al. (2002) to have a heterozygous deletion of 6 bp in the acceptor splice site region of intron 12 of the LBR gene. The deletion involved nucleotides -5 to -10 at the 3-prime end of intron 12. Although the mutation did not directly affect the consensus splice acceptor site, cDNA analysis showed that exon 13 was missing in the processed transcript sequence, which confirmed the functional disruption of this splice site.
Rhizomelic Skeletal Dysplasia with Pelger-Huet Anomaly
In 1 family (family P02) in the village of Gelenau studied by Hoffmann et al. (2002) in which the parents with PHA were heterozygous for the 6-bp deletion, their son (patient 8387) was presumably homozygous. This individual had neutrophils with round, nonsegmented nuclei and had presented at age 20 months with developmental delay, disproportionate body habitus, macrocephaly with prominent forehead, ventricular septal defect, and short metacarpals (SKPHA; 618019).
In 1 (family F10) of 11 families with Pelger-Huet anomaly (169400) residing in Gelenau, Hoffmann et al. (2002) found a splice acceptor site mutation in intron 2 of the LBR gene. The family showed a different haplotype from that of other families in the same region who shared a founder haplotype, and was found to have ancestry outside the region of Gelenau.
Waterham et al. (2003) described a fetus, the product of a consanguineous Turkish marriage, who presented with intrauterine growth retardation at 17 weeks' gestation and was found to have severe hydrops and short-limb skeletal dysplasia consistent with thanatophoric dysplasia. Intrauterine death occurred at 18 weeks, and delivery was induced. Fetal examination showed severe hydrops, extremely shortened edematous limbs, and postaxial polydactyly on both hands. Radiographic examination showed severe platyspondyly, short irregular ribs, a 'moth-eaten' aspect of scapular and pelvic bones, and very short tubular bones with angular diaphyses. Histopathology showed almost complete absence of ossification, severe disorganization of cartilage (with nodular calcification deposits), and defective or absent joint formation. On the basis of these findings, the diagnosis of Greenberg dysplasia (215140) was made. Elevated levels of cholesta-8,14-dien-3-beta-ol in cultured skin fibroblasts were consistent with deficiency of 3-beta-hydroxysterol delta(14)-reductase. Sequence analysis of the LBR gene identified a homozygous 7-bp substitution at nucleotide 1599 in exon 13, TCTTCTA-CTAGAAG, which resulted in a truncated protein. The mother showed classic Pelger-Huet anomaly (169400), which represents the heterozygous state of 3-beta-hydroxysterol delta(14)-reductase deficiency.
In a family from Slovakia, Best et al. (2003) found that Pelger-Huet anomaly (169400) was associated with a C-to-T transition in exon 3 of the LBR gene, changing codon 119 from CCG (pro) to CTG (leu) (P119L).
In a family from southern Italy, Best et al. (2003) identified association of Pelger-Huet anomaly (169400) with a splice acceptor site mutation in the LBR gene: IVS11-9A-G.
In an English man with Pelger-Huet anomaly (169400), Best et al. (2003) identified a heterozygous C-to-G transversion in exon 14 of the LBR gene, resulting in a pro569-to-arg (P569R) substitution.
In a 76-year-old Caucasian woman with Reynolds syndrome (613471), Gaudy-Marqueste et al. (2010) identified a heterozygous 1114C-T transition in exon 9 of the LBR gene, resulting in an arg372-to-cys (R372C) substitution in a highly conserved residue between the fourth and fifth transmembrane domains in the C terminus. The mutation was not found in 400 control chromosomes. The patient had a long history of Raynaud phenomenon, telangiectasia, mild cholestasis associated with mitochondrial autoantibodies consistent with primary biliary cirrhosis, and limited cutaneous scleroderma. Blood smear did not show Pelger-Huet anomaly. Studies of patient lymphoblastoid cells did not show abnormalities, but patient fibroblasts showed decreased LBR and decreased levels of lamin proteins, as well as dysmorphic nuclei with mottled chromatin. These findings suggested that the R372C mutation exerted a dominant-negative effect on LBR-interacting proteins, perhaps resulting from decreased stabilization of the mutant protein and increased proteosome-mediated degradation. Gaudy-Marqueste et al. (2010) hypothesized that the mutation caused a global perturbation of the nuclear envelope protein network.
In a fetus, the product of consanguineous Greek parents, with Greenberg dysplasia (GRBGD; 215140), Konstantinidou et al. (2008) identified a homozygous c.1639A-G transition in exon 13 of the LBR gene, resulting in an asn547-to-asp (N547D) substitution in a conserved residue in the C terminus. Each unaffected parent was heterozygous for the mutation, which was not found in 200 control Greek chromosomes.
Clayton et al. (2010) found that the consanguineous parents of a fetus with Greenberg dysplasia were heterozygous for the N547D mutation. Biologic material from the affected fetus was not available. The mutation was not found in 150 controls. The N547D substitution occurred at a highly conserved residue in the sterol reductase domain. Whereas wildtype LBR rescued a C14 sterol-reductase mutant yeast strain, N547D was only partially able to compensate. There was restoration of ergosterol, but transfected yeast also showed abnormal accumulation of 4-methylzymosterol and ignosterol.
In a fetus with Greenberg dysplasia (GRBGD; 215140), previously reported by Offiah et al. (2003), Clayton et al. (2010) identified compound heterozygosity for 2 mutations in the LBR gene: a c.1748G-A transition, resulting in an arg583-to-gln (R583Q) substitution at a highly conserved residue in the sterol reductase domain, and a 4-bp deletion (c.32delTGGT; 600024.0010), resulting in a frameshift and premature termination (Val11GlufsTer24). The R583Q mutation was not found in 150 controls. Analysis of parental peripheral blood cells showed that the mother, who carried the 4-bp deletion, had Pelger-Huet anomaly (169400), whereas the father, who carried the R583Q mutation, had normal neutrophils. Transfection of the R583Q mutation into a C14 sterol-reductase mutant yeast strain showed that the mutant protein was unable to compensate for the defect, and no ergosterol was produced. There was also abnormal accumulation of ignosterol.
For discussion of the 4-bp deletion in the LBR gene (c.32delTGGT) that was found in compound heterozygous state in a fetus with Greenberg dysplasia (GRBGD; 215140) by Clayton et al. (2010), see 600024.0009. The mother of the fetus was heterozygous for the 4-bp deletion and had Pelger-Huet anomaly (169400).
In a fetus with Greenberg dysplasia (GRBGD; 215140), Clayton et al. (2010) identified a homozygous 1-bp deletion (c.1402delT) in the LBR gene, resulting in a frameshift and premature termination (Tyr468ThrfsTer475). The mutation was not present in 150 controls. The numbering of the mutation was discordant in the text (c.1492delT) versus the supplementary material (c.1402delT).
In a 12-year-old adopted girl with mild skeletal anomalies and Pelger-Huet anomaly (SKPHA; 618019), Borovik et al. (2013) identified compound heterozygous mutations in the LBR gene: an insertion/deletion mutation (c.631_653delinsTGATGAGAAA) in exon 6, resulting in a frameshift and a premature termination codon (Ile218AspfsTer19), and a c.1757G-A transition in exon 14, resulting in an arg586-to-his (R586H; 600024.0013) at a conserved residue. The c.1757G-A variant was not found in 1,092 individuals in the 1000 Genome Project database or in 6,503 individuals in NHLBI Exome Sequencing Project database. The authors noted that the patient had dumbbell-shaped neutrophil nuclei characteristic of heterozygotes, suggesting that one of the mutations does not result in complete loss of LBR protein. No functional studies were reported.
For discussion of the c.1757G-A transition in the LBR gene, resulting in an arg586-to-his (R586H) substitution, that was found in compound heterozygous state in a patient with mild skeletal anomalies with Pelger-Huet anomaly (SKPHA; 618019) by Borovik et al. (2013), see 600024.0012.
In a 15-year-old boy with mild skeletal anomalies with Pelger-Huet anomaly (SKPHA; 618019), Sobreira et al. (2014) identified compound heterozygous mutations in the LBR gene: an arg76-to-ter (R76X) substitution in exon 3 and an asn547-to-ser (N547S; 600024.0015) substitution in exon 13. The mother and the unaffected brothers of the proband were heterozygous for the N547S mutation, and the father did not have either mutation. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. No functional studies were reported.
For discussion of the asn547-to-ser (N547S) mutation in the LBR gene that was identified in a boy with mild skeletal anomalies with Pelger-Huet anomaly (SKPHA; 618019) by Sobreira et al. (2014), see 600024.0014.
In a girl (patient 1) with short stature, spondylometaphyseal dysplasia, spontaneously improving rhizomelic limb shortening and Pelger-Huet anomaly (SKPHA; 618019), Thompson et al. (2019) identified compound heterozygous mutations in the LBR gene: a c.1504C-G transversion in exon 12 of the LBR gene, resulting in an arg502-to-gly (R502G) substitution, and a c.1748G-T transversion in exon 14, resulting in an arg583-to-leu (R583L) substitution (600024.0017). Her father was heterozygous for the mutation.
For discussion of the c.1748G-T transversion in exon 14 of the LBR gene, resulting in an arg58-to-leu (R58L) substitution, that was identified in compound heterozygous state in a patient with rhizomelic skeletal dysplasia with Pelger-Huet anomaly (SKPHA; 618019) by Thompson et al. (2019), see 600024.0016.
In 2 middle-aged sisters with short stature with predominant rhizomelia of the upper limbs and mesomelia of the lower limbs without Pelger-Huet anomaly (SKPHA; 618019), Collins et al. (2020) identified a homozygous c.1366C-G transversion (c.1366C-G, NM_002296.4) in exon 11 of the LBR gene, resulting in a leu456-to-val (L456V) substitution.
In a patient, born to consanguineous Turkish parents, with Greenberg dysplasia (GRBGD; 215140), who had a presumed diagnosis of achondrogenesis 1A, Wehrle et al. (2018) detected a homozygous c.366+1G-T transversion that abolishes the splice donor site of exon 3. The nucleotide change was validated by Sanger sequencing. The parents were heterozygous for the mutation. Molecular characterization of patient-derived fibroblasts demonstrated missplicing of exon 3, resulting in a frameshift and premature termination (Glu111SerfsTer39). LBR mRNA was barely detectable by real-time PCR, compatible with nonsense-mediated decay. Western blot analysis and immunofluorescence demonstrated that the fetal cells were completely devoid of LBR protein.
In 2 sib fetuses with Greenberg dysplasia (GRBGD; 215140), Giorgio et al. (2019) identified a homozygous c.1379A-G transition in the LBR gene, resulting in an asp460-to-arg (D460R) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
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