Mutation Analysis of LMX1B Gene in Nail-Patella Syndrome Patients

Abstract

Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports 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.

Genotype–phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy

“…Two other patients with the same mutation have been reported, both are without nephropathy. 43 In two other familial cases with a similar LMX1B mutation (672 þ 1G4T), one patient had nephropathy. 43 In the current study, the high prevalence of nephropathy in patients with HD mutations is mainly attributable to the large family 26 with a mutation 672 þ 1G4A (8/15 nephropathy).…”

“…43 In two other familial cases with a similar LMX1B mutation (672 þ 1G4T), one patient had nephropathy. 43 In the current study, the high prevalence of nephropathy in patients with HD mutations is mainly attributable to the large family 26 with a mutation 672 þ 1G4A (8/15 nephropathy). However, if we exclude family 26 from statistical analysis, the relationship between nephropathy and the location of the LMX1B mutation is still significant, emphasizing the presence of this association in additional NPS families (Tables 3 and 4).…”

“…This is in contrast with a previous compilation of LMX1B mutations in NPS, which revealed no such relationship: nephropathy was reported in 55.2% (16/29) of individuals from 20 families with mutations identified in the HD of LMX1B and in 55.6% (5/ 9) of subjects from four families mutations located within LIM-A or LIM-B domains. 43 However, in the latter study, phenotypic information was provided by anamnestic history and/or based on qualitative urinanalysis, and no definition of nephropathy was mentioned. Two other patients with the same mutation have been reported, both are without nephropathy.…”

Deletion of a branch-point consensus sequence in the LMX1B gene causes exon skipping in a family with nail patella syndrome

“…The syndrome is inherited in an autosomal dominant manner and has been shown to result from mutations in the LIM-homeodomain encoding LMX1B gene. [3][4][5][6] The LMX1B transcription factor plays a role in defining the development of dorsal specific structures during limb development; 7 its role in other organs is unclear. Analysis of over 60 LMX1B mutations in NPS families supports the hypothesis that the syndrome results from haploinsufficiency due to loss of function mutation.…”

“…Analysis of over 60 LMX1B mutations in NPS families supports the hypothesis that the syndrome results from haploinsufficiency due to loss of function mutation. [3][4][5][6] During the search for LMX1B mutations causing NPS, a 17bp deletion was identified upstream of the 3' splice consensus which removed a consensus branchpoint sequence. The effect of this deletion on the splicing of LMX1B RNA was studied further.…”