Alternative titles; symbols
HGNC Approved Gene Symbol: LMX1B
SNOMEDCT: 22199006, 236527004; ICD10CM: Q87.2;
Cytogenetic location: 9q33.3 Genomic coordinates (GRCh38): 9:126,613,928-126,701,032 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q33.3 | Focal segmental glomerulosclerosis 10 | 256020 | Autosomal dominant | 3 |
| Nail-patella syndrome | 161200 | Autosomal dominant | 3 |
The LMX1B gene encodes a transcription factor that belongs to the LIM-homeodomain family of proteins. These proteins are viral for the normal development of dorsal limb structures in vertebrates, components of the renal glomerular filtration barrier, and the anterior segment of the eye (summary by Isojima et al., 2014 and Hall et al., 2017).
LIM-homeodomain proteins are characterized by the presence of 2 tandem cysteine/histidine-rich, zinc-binding LIM domains. LMX1 (600298), a LIM-homeodomain-containing protein expressed selectively in insulin-producing beta cell lines, has been shown to activate insulin gene transcription. Iannotti et al. (1997) searched a human EST database with hamster LMX1 sequences to isolate the human LMX1 gene for physical mapping and identification of polymorphic markers. They obtained 2 highly homologous sequences, originally identified by exon trapping of human chromosome 9 (Church et al., 1994), and showed that the ESTs represented a closely related but distinct gene, designated LMX1.2 or LMX1B. Iannotti et al. (1997) found that the sequence of a 482-bp RT-PCR product of human LMX1B and that of the corresponding hamster LMX1 were 92% identical at the amino acid level and that the DNA-binding domains were 100% identical at the amino acid level. They used the human chromosome 9 EST to rescreen the hamster pancreatic islet beta cell library and isolated hamster LMX1B. Sequence comparison suggested that human and hamster LMX1B and chicken LMX1 (Vogel et al., 1995) are homologs of the same gene, which is closely related to hamster LMX1. Iannotti et al. (1997) performed RT-PCR analysis on total RNAs from 11 adult human tissues and found expression of LMX1B in most of the tissues, with highest levels in testis, thyroid, duodenum, skeletal muscle, and pancreatic islets.
Dreyer et al. (1998) isolated an LMX1B cDNA and stated that the open reading frame encodes 372 amino acids and contains 2 N-terminal zinc-binding LIM domains, 1 homeodomain, and a C-terminal glutamine-rich domain. The mouse and human sequences are 99% identical. Northern blot analysis of RNA from human fetal and adult tissues revealed a major 7.0-kb transcript abundant in fetal and adult kidney.
Dunston et al. (2004) identified an upstream start codon in the LMX1B gene that is in-frame with the previously determined open reading frame, extending the protein to 395 or 402 amino acids, depending on exon 7 splice-site selection. Upstream of this start codon are 2 additional short open reading frames.
Dreyer et al. (2000) noted strong expression of Lmx1b in dorsal mesenchymal tissues (precursors of muscle, tendons, joints, and patella) and also in anterior structures of the murine limb by in situ hybridization, mimicking the anterior to posterior gradient of joint and nail dysplasia observed in patients with nail-patella syndrome (NPS; 161200). Transfection studies showed that both the LIM domain-interacting protein LDB1 (603451) and the helix-loop-helix protein E47/shPan1 (147141), regulated LMX1B action. While cotransfections of E47/shPan1 with LMX1B resulted in a synergistic effect on reporter activity, LDB1 downregulated LMX1B-mediated transactivation irrespective of E47/shPan1. Mutant LMX1B proteins containing human mutations affecting each of the helices or the N-terminal arm of the homeodomain abolished transactivation, while LIM B domain and truncation mutations retained residual activity. These mutations failed to act in a dominant-negative manner on wildtype LMX1B in mixing studies, thereby further supporting haploinsufficiency as the mechanism underlying NPS pathogenesis.
Kania et al. (2000) showed that Lim1 (LHX1; 601999) and Lmx1b control the initial trajectory of motor axons in the developing mammalian limb. The expression of Lim1 by a lateral set of lateral motor column (LMC) neurons ensured that their axons selected a dorsal trajectory in the limb. In a complementary manner, the expression of Lmx1b by dorsal limb mesenchymal cells was shown to control the dorsal and ventral axonal trajectories of medial and lateral LMC neurons. In the absence of these 2 proteins, motor axons appeared to select dorsal and ventral trajectories at random. Thus, LIM homeodomain proteins act within motor neurons and cells that guide motor axons to establish the fidelity of a binary choice in axonal trajectory.
Morello et al. (2001) reported that, in Lmx1b -/- mice, expression of both the alpha-3 and alpha-4 chains of type IV collagen is strongly diminished in glomerular basement membrane, whereas that of alpha-1, alpha-2, and alpha-5 type IV collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 (120131) and upregulates reporter constructs containing this enhancer-like sequence. These data indicated that LMX1B directly regulates the coordinated expression of the alpha-3(IV) and alpha-4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in glomerular basement membrane contributes to the renal pathology and nephrosis in nail-patella syndrome.
Ding et al. (2003) presented evidence suggesting that Lmx1b is required for the development of 5-HT (5-hydroxytryptamine) neurons in the central nervous system in mice, and that Lmx1b acts as a critical mediator downstream of Shh (600725) and Nkx2.2 (604612) in a signaling cascade to direct specification and/or differentiation of 5-HT neurons.
Johnson and Tabin (1997) reviewed the role of this gene, which they referred to as LMX1, and others in limb development.
Marini et al. (2005) demonstrated an interaction between LMX1B and the PAX2 gene (167409) using both direct yeast 2-hybrid assays and coimmunoprecipitation studies. Experiments with deletion constructs indicated that the LMX1B homeodomain interacted with the PAX2 homeodomain. Marini et al. (2005) suggested that PAX2 may be a modifier gene in NPS.
By analyzing Lmx1b conditional knockout mice, Donovan et al. (2019) showed that Lmx1b was required for formation of both ascending and descending 5-HT axon projection pathways, as Lmx1b deficiency in 5-HT neurons resulted in delayed primary pathway formation followed by a profound failure of ascending axons to selectively route into preexisting fiber tracts. Stage-specific knockdown of Lmx1b at different early postnatal timepoints of mouse development revealed that Lmx1b acted temporally at successive stages to control 5-HT axon primary outgrowth, selective routing, and terminal arborization. RNA-sequencing analysis revealed that Lmx1b controlled axon-related transcriptomes and identified an ascending-specific axonal Lmx1b-to-Pet1 (FEV; 607150) regulatory cascade. Lmx1b acted through Pet1 continually over an extended postnatal period to control stage-specific gene expression and to generate both early and late 5-HT terminal arbor patterns in different forebrain regions.
Vollrath et al. (1998) determined that the LMX1B gene contains at least 8 exons in a genomic region with high CG content.
Dunston et al. (2004) determined that the LMX1B transcription start site is located within a cluster of 4 CpG islands and is not associated with a consensus TATA box. The 5-prime UTR contains CCAAT boxes, a basic transcription element, and binding sites for SP1 (189906), OCT1 (164175), and TCF (142410)/LEF1 (153245).
By PCR analysis of rodent-human somatic cell hybrid DNA, Iannotti et al. (1997) confirmed the mapping of the LMX1 gene to chromosome 1 and the LMX1B gene to chromosome 9. The authors identified a simple sequence repeat polymorphisms in a P1 genomic clone containing LMX1B and used the resulting polymorphic markers to construct a genetic linkage map that localized LMX1B to 9q32-q34.1.
Nail-Patella Syndrome
Dreyer et al. (1998) identified de novo heterozygous mutations in the LMX1B gene (161200.0001-161200.0003) in 3 unrelated patients with nail-patella syndrome (NPS; 161200). Functional studies showed that one of these mutations disrupted sequence-specific DNA binding, while the other 2 mutations resulted in premature termination of translation. All 3 patients had presented in early childhood with nail dysplasia involving at least the thumbs, elbow stiffness with limitation of pronation and supination, and poorly ossified, malformed patellae. They also had classic radiographic features, including iliac flaring and iliac horns.
Vollrath et al. (1998) sequenced a large segment of LMX1B from the genomic DNA of probands from 4 families with nail-patella syndrome and open angle glaucoma (OAG; see 137760) and identified 4 mutations: 2 stop codons, a deletion causing a frameshift, and a missense mutation in a functionally important residue. The presence of these putative loss-of-function mutations in the DNA of individuals with NPS indicated that haploinsufficiency of LMX1B underlies this disorder. The results helped explain the high degree of variability in the NPS phenotype, and suggested that the skeletal defects in NPS are a result of the diminished dorsoventral patterning activity of LMX1B protein during limb development. The results further suggested that the NPS and OAG phenotypes in the families studied resulted from mutations in a single gene, LMX1B. Although renal abnormalities accompanying NPS were well known, the cosegregation of open angle glaucoma with NPS in other families (Lichter et al., 1997) was a less well-known finding.
McIntosh et al. (1998) screened 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supported the hypothesis that NPS is the result of haploinsufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations.
Clough et al. (1999) stated that a total of 64 point mutations and small deletions or insertions in the LMX1B gene had been reported and that they were concentrated within either the LIM or homeodomains. No nail-patella syndrome mutations had been observed within the C-terminal third of the coding sequence, suggesting that mutations in this region are not inactivating. These findings supported the hypothesis that NPS results from a 50% reduction in LMX1B function via a reduction in synthesis, disruption of secondary structure, or failure to bind DNA.
Dunston et al. (2004) identified 47 additional mutations within the coding region of the LMX1B gene, as well as 9 deletions of large portions of the gene. No mutations were identified in the promoter or in highly conserved intronic sequences.
Using multiplex ligation-probe amplification (MLPA) analysis, Bongers et al. (2008) identified a heterozygous deletion of the entire LMX1B gene (602575.0013) in 2 unrelated patients with nail-patella syndrome. The phenotype was similar to other reported cases with point or truncating mutations. The findings confirmed that haploinsufficiency of LMX1B is the pathogenic mechanism in nail-patella syndrome.
Focal Segmental Glomerulosclerosis 10
In 5 affected members of a large multigenerational family (family F) with focal segmental glomerulosclerosis-10 (FSGS10; 256020), Boyer et al. (2013) identified a heterozygous missense mutation in the LMX1B gene (R246Q; 602575.0014). The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Direct sequencing of the LMX1B gene in a cohort of 73 unrelated families with a similar phenotype identified a heterozygous R246Q mutation in an affected mother and daughter (family V) and a heterozygous R246P (602575.0015) mutation in an affected father and daughter (family B). Neither variant was present in the Exome Sequencing Project. Functional studies of the variants and studies of patient cells were not performed, but Boyer et al. (2013) noted that residue R246 is highly conserved and located in the homeobox domain, which is important for DNA binding and transcriptional activation.
In a 6-year-old Japanese girl with FSGS10, Isojima et al. (2014) identified a de novo heterozygous R246Q substitution in the LMX1B gene. The mutation, which was found by direct sequencing of the LMX1B gene, was not present in the dbSNP database or among Japanese controls. In vitro functional expression studies showed that the mutation partially impaired transcriptional activity of LMX1B compared to controls, but not to the extent as mutations associated with NPS. There was no evidence for a dominant-negative effect, and the authors postulated haploinsufficiency. Renal biopsy from the patient showed podocyte effacement, a thickened glomerular basement membrane (GBM) due to abnormal deposition of type III collagen, and altered expression of CD2AP (604241), which plays a role in podocyte development and cytoskeleton remodeling.
In 18 affected members from 2 large multigenerational families (DUK35705 and DUK34319) with FSGS10, Hall et al. (2017) identified a heterozygous R246Q mutation in the LMX1B gene. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In vitro functional expression studies in human podocyte cell lines transfected with the mutation showed altered expression of certain key podocyte genes, suggesting that the mutation may exert a haploinsufficiency effect on the transcriptional regulation of these genes. However, additional studies indicated that the R246Q mutation exerted a dominant-negative effect on certain WT1 (607102) isoforms, which may have also caused alterations in the expression of podocyte-related genes. Hall et al. (2017) noted that the renal glomerular phenotype observed in these patients includes a wide variety of light microscopic findings, including focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and even immune complex glomerulonephritis.
A heterozygous R246Q mutation was identified in patients with FSGS10 by Lei et al. (2020) and Pinto e Vairo et al. (2020).
Bongers et al. (2005) performed LMX1B mutation analysis and comprehensive examinations in 106 subjects from 32 NPS families and found that individuals with an LMXB1 mutation located in the homeodomain showed significantly more frequent and higher values of nephropathy and proteinuria than subjects with mutations in the LIM domains. No clear genotype-phenotype association was apparent for extrarenal manifestations.
Dorsoventral limb patterning in vertebrates is controlled by the LIM-homeodomain protein Lmx1b, which is expressed in a spatially and temporally restricted manner along the dorsoventral limb axis (Vogel et al., 1995). Chen et al. (1998) described a phenotype resulting from targeted disruption of Lmx1b in mice. The results demonstrated that Lmx1b is essential for the specification of dorsal limb fate at both the zeugopodal and autopodal levels with prominent phenotypes including absence of nails and patellae. Using an interspecific backcross panel, Pilz et al. (1994) mapped the Lmx1b gene to the distal portion of mouse chromosome 2 in a region syntenic to human 9q34, where the nail-patella syndrome gene is located. Furthermore, kidneys of Lmx1b mutant mice exhibited pathologic changes similar to those observed in nail-patella syndrome.
Hamano et al. (2002) characterized the renal defects of mice deficient in Lmx1b, which controls the expression of several glomerulus-specific proteins. Lmx1b-null mice died immediately after birth with massive glomerular vascular leaks. Glomerular basement membranes of these mice showed altered architecture, reduced expression of the type IV collagens alpha-3 (120070) and alpha-4 (COL4A4), and altered expression of the slit diaphragm proteins nephrin (602716) and podocin (604766).
In a patient with nail-patella syndrome (NPS; 161200) who presented at 5 years of age with elbow contractures without evidence of ocular or renal abnormalities, Dreyer et al. (1998) found a C-to-A transversion in the LMX1B gene that resulted in substitution of lysine for asparagine at amino acid position 246.
Dunston et al. (2004) identified an upstream start codon in-frame with the published open reading frame of the LMX1B gene, revealing an additional 23 amino acids in-frame with the reported start codon; thus, this mutation results in an asn269-to-lys (N269K) substitution.
In a patient with typical nail-patella syndrome (NPS; 161200), who presented at 6 years with joint stiffness and irregular pigmentation of the iris, but without evidence of kidney dysfunction, Dreyer et al. (1998) found a C-to-T transition in the LMX1B gene that resulted in an arg198-to-ter substitution was predicted to cause premature termination of the polypeptide with abolition of both the homeodomain and the putative glutamine-rich activation domain.
Dunston et al. (2004) identified an upstream start codon in-frame with the published open reading frame of the LMX1B gene, revealing an additional 23 amino acids in-frame with the reported start codon; thus, this mutation results in an arg221-to-ter (R221X) substitution.
In a patient with classic features of nail-patella syndrome (NPS; 161200) who presented in infancy with proteinuria and ultimately developed nephrotic syndrome, Dreyer et al. (1998) identified a single nucleotide A insertion in the LMX1B gene, resulting in a frameshift mutation disrupting the reading frame at codon 233 in the homeodomain and predicting translation termination at codon 327 in the glutamine-rich C-terminal domain (713insA). Light microscopic analysis of a kidney biopsy from this patient showed only mild interstitial fibrosis; ultrastructural studies revealed thickened and split glomerular basement membranes, and fusion and hyperplasia of foot processes similar to that identified in Lmx1b -/- mice.
In a 4-generation family (UM:47) of German ancestry, Vollrath et al. (1998) found typical features of nail-patella syndrome (NPS; 161200) in all members who had open angle glaucoma, as well as in members who did not have POAG. Proteinuria was not present. Age at onset of glaucoma ranged from 18 to 41 years (mean, 32 years). The proband was found to be heterozygous for a G-to-T transversion in exon 3 of the LMX1B gene that resulted in a cys95-to-phe amino acid substitution in the LIM2 domain of the protein.
In a 4-generation family (UM:65) of French and Irish ancestry, Vollrath et al. (1998) found that the proband and 6 other individuals with glaucoma also had nail-patella syndrome (NPS; 161200). Age at onset of glaucoma ranged from birth to 54 years (mean, 24 years). Proteinuria was not found in family members who were screened, but medical records indicated that the proband's mother had proteinuria and kidney disease. The proband of family UM:65 was heterozygous for a 2-bp deletion in exon 2 (233delTG) of the LMX1B gene, predicting a severely truncated protein that lacks part of the LIM1 domain and all of the LIM2 and homeodomains, and contains a stretch of 44 N-terminal amino acid residues generated from an incorrect reading frame.
Vollrath et al. (1998) reported that members of family UM:68 with nail-patella syndrome (NPS; 161200) and open angle glaucoma had features of NPS that were said to have come from a Cherokee Indian ancestor. Age at onset of OAG ranged from 40 to 77 years (mean, approximately 56 years). In contrast to the other 3 families studied by Vollrath et al. (1998), all of the individuals with NPS in UM:68 were reported to have proteinuria. The proband of UM:68 was heterozygous for a C-to-T transition in exon 2 of the LMX1B gene that created a premature stop codon (gln59 to ter).
Vollrath et al. (1998) described an LMX1B mutation, arg208 to ter, as the cause of nail-patella syndrome (NPS; 161200) and open angle glaucoma in a Caucasian family (UM:310). No proteinuria was known in the family. As in the other families studied by Vollrath et al. (1998), the severity of fingernail anomalies ranged from mild ridging to hypoplasia and aplasia. Elbow mobility was likewise variable. Age at onset of glaucoma ranged from 40 to 50 years (mean, 45 years).
McIntosh et al. (1998) described a 599G-A transition in the LM1B gene, resulting in an arg200-to-gln amino acid substitution in the homeodomain, in 5 presumably unrelated families with nail-patella syndrome (NPS; 161200). The mutation ablated a MspI restriction site. Putatively the gene had an effect on DNA binding. The recurrence of this mutation was not unexpected, since it was the result of a transition at a CpG dinucleotide.
In a family in which 3 members had nail-patella syndrome (NPS; 161200), McIntosh et al. (1998) demonstrated a splice site mutation, 672+1G-A, in the homeodomain of the LMX1B gene, resulting in loss of exon 4, a frameshift, and a premature termination codon. The mutation occurred in the same codon as another splice mutation (602575.0010).
In a family in which 2 members had nail-patella syndrome (NPS; 161200), McIntosh et al. (1998) demonstrated a splice site mutation, 672+1G-T, in the homeodomain of the LMX1B gene, which resulted in loss of exon 4, a frameshift, and a premature termination codon. The same nucleotide was involved as in another splice mutation, 672+1G-A (602575.0009).
In 2 affected members of a family with nail-patella syndrome (NPS; 161200), McIntosh et al. (1998) identified a 676C-T transition in the LMX1B gene, resulting in an arg226-to-ter substitution in the homeodomain.
Hamlington et al. (2000) found that the basis of the nail-patella syndrome (NPS; 161200) in an extensively affected kindred was a 17-bp deletion in intron 1 starting 37 bp upstream of exon 2 of the LMX1B gene. The deletion removed a recognition sequence for the restriction enzyme EagI; restriction digestion of PCR-amplified DNA from 14 affected and 11 unaffected members indicated that the deletion was found only in persons with NPS and was not found in 50 unrelated individuals from an unaffected control population. The deletion encompassed a consensus branchpoint sequence. RNA analysis demonstrated that deletion of the branchpoint sequence resulted in skipping of the downstream exon. Hamlington et al. (2000) suggested a mechanism to explain this phenomenon.
In 2 unrelated patients with nail-patella syndrome (NPS; 161200), Bongers et al. (2008) identified a heterozygous deletion of the entire LMX1B gene. The deletion was de novo and limited to the LMX1B gene in 1 patient, whereas the deletion was inherited and included some flanking regions in the other patient. The phenotype was similar to other reported cases with point or truncating mutations. The findings confirmed that haploinsufficiency of LMX1B is the pathogenic mechanism in nail-patella syndrome.
In 5 affected members of a large multigenerational family (family F) of European descent with focal segmental glomerulosclerosis-10 (FSGS10; 256020), Boyer et al. (2013) identified a heterozygous c.737G-A transition in exon 4 of the LMX1B gene, resulting in an arg246-to-gln (R246Q) substitution at a highly conserved residue in the homeodomain, which is important for DNA binding and necessary for transcriptional activation. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. The variant was not present in the Exome Sequencing Project database. Two affected members of another European family (family V) with the same phenotype were also found to carry a heterozygous R246Q mutation. Functional studies of the variant and studies of patient cells were not performed, but Boyer et al. (2013) hypothesized that the mutation might interfere with DNA binding.
In a 6-year-old Japanese girl with FSGS10, Isojima et al. (2014) identified a de novo heterozygous arg246-to-gln (R246Q) substitution in the LMX1B gene. The mutation, which was found by direct sequencing of the LMX1B gene, was not present in the dbSNP database or among Japanese controls. In vitro functional expression studies showed that the mutation partially impaired transcriptional activity of LMX1B compared to controls, but not to the extent as mutations associated with NPS. There was no evidence for a dominant-negative effect, and the authors postulated haploinsufficiency. Renal biopsy from the patient showed podocyte effacement, a thickened glomerular basement membrane (GBM) due to abnormal deposition of type III collagen, and altered expression of CD2AP (604241), which plays a role in podocyte development and cytoskeleton remodeling.
In 18 affected members of 2 large multigenerational families (DUK35705 and DUK34319) with FSGS10, Hall et al. (2017) identified a heterozygous R246Q mutation in the LMX1B gene. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In vitro functional expression studies in human podocyte cell lines transfected with the mutation showed altered expression of certain key podocyte genes, suggesting that the mutation may exert a haploinsufficiency effect on the transcriptional regulation of these genes. However, additional studies indicated that the R246Q mutation exerted a dominant-negative effect on certain WT1 (607102) isoforms, which may have also caused alterations in the expression of podocyte-related genes. Hall et al. (2017) noted that the renal glomerular phenotype observed in these patients includes a wide variety of light microscopic findings, including focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and even immune complex glomerulonephritis.
Pinto e Vairo et al. (2020) identified a heterozygous c.737G-A transition (c.737G-A, NM_002316.3) in the LMX1B gene, resulting in a R246Q substitution, in a 65-year-old woman with FSGS10 and a family history of chronic kidney disease.
Lei et al. (2020) identified heterozygosity for the R246Q mutation in patients from 2 families with FSGS10.
In a father and daughter of European descent (family B) with focal segmental glomerulosclerosis-10 (FSGS10; 256020), Boyer et al. (2013) identified a heterozygous c.737G-C transversion in exon 4 of the LMX1B gene, resulting in an arg246-to-pro (R246P) substitution at a highly conserved residue in the homeodomain, which is important for DNA binding and necessary for transcriptional activation. The mutation, which was found by direct sequencing of the LMX1B gene, was not present in the Exome Sequencing Project database. This family was ascertained from a cohort of 73 unrelated families with a similar phenotype. Functional studies of the variant and studies of patient cells were not performed, but Boyer et al. (2013) hypothesized that the mutation might interfere with DNA binding.
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