LOSS-OF-FUNCTION MUTATIONS IN THE LIM-HOMEODOMAIN GENE, LMX1B, IN NAIL-PATELLA SYNDROME

Nail-patella syndrome (NPS) is an inherited developmental disorder mos t commonly involving maldevelopment of the fingernails, kneecaps and e lbow joints. NPS exhibits wide variation in phenotypic expression with in and among families with respect to these features. Other skeletal a bnormalities such as hip dislocation and club foot have also been repo rted 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 tran scription factor of the LIM-homeodomain type with homologs that are im portant for limb development in vertebrates, was mapped to the same ge neral location as NPS at 9q34. We sequenced a targe segment of LMX1B f rom the genomic DNA of probands from four families with NPS and GAG, a nd identified four mutations: two stop codons, a deletion causing a fr ameshift and a missense mutation in a functionally important residue, The presence of these putative loss-of-function mutations in the DNA o f individuals with NPS indicates that haploinsufficiency of LMX1B unde rlies this disorder. These findings help to explain the high degree of variability in the NPS phenotype, and suggest that the skeletal defec ts in NPS are a result of the diminished dorsoventral patterning activ ity of LMX1B protein during limb development, The results further sugg est that the NPS and OAG phenotypes in the families studied result fro m mutations in a single gene, LMX1B.