Identification of LMX1B gene point mutations in Italian patients affected with Nail-Patella syndrome

Nail-Patella syndrome, or osteo-onychodysplasia, is an autosomal dominant d isorder characterized by nail dysplasia, absent or hypoplastic patellae, il iac horns and nephropathy. Previous studies have demonstrated linkage of th e Nail-Patella locus with polymorphic markers on human chromosome 9q34. Rec ently, point mutations in the LMX1B gene have been identified in Nail-Patel la patients and in families with recurrence of Nail-Patella syndrome and op en-angle glaucoma. We describe here the identification of additional point mutations in the LMX1B gene in a set of Italian patients affected with Nail -Patella syndrome: two deletions of 1 and 2 bp causing a frameshift in two sporadic patients and nonsense mutations in two familial and one sporadic c ases have been identified. All the mutations affect the homeodomain of the LMX1B protein and could cause the Nail-Patella syndrome through a loss of f unction as well as a dominant negative effect. Haplotype analysis in the tw o familial cases carrying the same stop codon mutation suggests the presenc e of a founder effect. Finally, analysis of cDNA clones obtained from human fetal kidney has revealed the existence of two different transcripts of LM X1B gene likely due to an alternative splicing.