Disease relevance of LMX1B

• Mutations in LMX1B cause nail-patella syndrome (NPS), an autosomal dominant disease with skeletal abnormalities, nail hypoplasia, and nephropathy [1].
• Nail-patella syndrome (NPS), an autosomal dominant disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns, and often associated with nephropathy and, less frequently, with open angle glaucoma, is caused by mutations in the LMX1B gene [2].
• Individuals with an LMX1B mutation located in the homeodomain showed significantly more frequent and higher values of proteinuria compared to subjects carrying mutations in the LIM domains [3].

High impact information on LMX1B

• Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome [4].
• Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence [4].
• These data demonstrate a unique role for LMX1B in renal development and in patterning of the skeletal system, and suggest that alteration of Lmx1b/LMX1B function in mice and humans results in similar phenotypes [5].
• Using gel shift assays, we demonstrated that LMX1B bound to two AT-rich sequences in the promoter region of NPHS2, the gene encoding podocin [6].
• The finding that this disease is caused by mutations in the transcription factor LMX1B, which in the kidney is expressed exclusively in podocytes, offers the opportunity for a better understanding of the renal pathogenesis [6].

Biological context of LMX1B

• While it is a unique mesenchymal determinant of dorsal limb patterning during vertebrate development, the mechanism by which LMX1B mutations generate the NPS phenotype has not been addressed at a transcriptional level or correlated with its spatial pattern of gene expression [7].
• LMX1B transactivation and expression in nail-patella syndrome [7].
• We sequenced a large segment of LMX1B from the genomic DNA of probands from four families with NPS and OAG, and identified four mutations: two stop codons, a deletion causing a frameshift and a missense mutation in a functionally important residue [8].
• Analysis of SNP haplotypes across the LMX1B gene demonstrated association between the haplotype of the mutant allele and the variability in the nail score (p = 0.024) [9].
• This indicates that the incidence and severity of nephropathy within this family cannot be attributed to the LMX1B genotype [10].

Anatomical context of LMX1B

• The glomerular basement membrane fibrillar material was specifically labeled with anti-type III collagen antibodies, suggesting a possible regulation of type III collagen expression by LMX1B [11].
• Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed [12].

Associations of LMX1B with chemical compounds

• Three of the mutations are very likely to result in truncated LMX1B proteins, three are predicted to influence sequence-specific DNA binding, and one is presumed to prevent the formation of a stable protein by abolishing the Zn(II) binding site of the protein [10].

Regulatory relationships of LMX1B

• On the one hand, FGF8 widens beyond the neural folds the competence of the neuroepithelium to develop a RP by inducing the expression of LMX1B and WNT1 [13].

Other interactions of LMX1B

• These findings indicate that heterozygous mutations of LMX1B do not appear to dramatically affect the expression of type IV collagen chains, podocin, or CD2AP in NPS patients [11].
• Confirmation of CLIM2/LMX1B interaction by yeast two-hybrid screening and analysis of its involvement in nail-patella syndrome [2].
• The LMX1B and the SHOX genes were also evaluated considering the absent patellae and short stature, respectively, and were found normal as well [14].
• Results are presented on the interaction between LMX1B and PAX2 proteins, obtained by both direct yeast two-hybrid assay and coimmunoprecipitation [15].
• Identification of a human LMX1 (LMX1.1)-related gene, LMX1.2: tissue-specific expression and linkage mapping on chromosome 9 [16].

References