Loss-of-Function Mutations in the LIM-Homeodomain Gene, LMX1B, in Nail-Patella Syndrome

Abstract

Nail-patella syndrome (NPS) is an inherited developmental disorder most commonly involving maldevelopment of the fingernails, kneecaps and elbow joints. NPS exhibits wide variation in phenotypic expression within and among families with respect to these features. Other skeletal abnormalities such as hip dislocation and club foot have also been reported in some individuals with NPS. There is an association between NPS and renal disease, and between NPS and open-angle glaucoma (OAG), but it is not known whether mutations in a single gene cause the observed skeletal, renal and ophthalmic abnormalities. Recently, LMX1B , a transcription factor of the LIM-homeodomain type with homologs that are important for limb development in vertebrates, was mapped to the same general location as NPS at 9q34. 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. The presence of these putative loss-of-function mutations in the DNA of individuals with NPS indicates that haploinsufficiency of LMX1B underlies this disorder. These findings help to explain the high degree of variability in the NPS phenotype, and suggest that the skeletal defects in NPS are a result of the diminished dorsoventral patterning activity of LMX1B protein during limb development. The results further suggest that the NPS and OAG phenotypes in the families studied result from mutations in a single gene, LMX1B.

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

“…NPS is caused by heterozygous mutations in the gene encoding the LIM-homeodomain transcription factor LMX1B. 1,2 Studies in Lmx1b À/À mice have shown that Lmx1b plays a crucial role in dorso-ventral patterning of the limb, patterning of the skull, morphogenesis and function of the podocytes and the glomerular basement membrane (GBM), and development of the anterior segment of the eye. 3 -8 In the central nervous system, Lmx1b is involved in developing dopaminergic and serotonergic neurons of the hindbrain and the midbrain, and dorsal interneurons of the spinal cord.…”

Transcriptional regulation of podocyte disease

“…[18][19][20] In the kidney, Lmx1b is expressed in podocytes. Lmx1b protein has two zincbinding LIM domains at the amino terminus and a homeodomain in the middle.…”

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.…”