Molecular analysis of the CLCN5 gene in Dent's disease: first mutation identified in a patient from South America.

Background: Dent's disease is a rare renal tubular disorder characterized by low-molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and eventual renal failure. The selective loss of low-molecular weight proteins points to a defect of the proximal tubule, where filtered proteins are normally reabsorbed by endocytosis. The disease tends to present in childhood or early adult life, and males are more severely affected than females. The disease is caused by mutations in CLCN5 or OCRL1, both on the X chromosome, which code for the chloride/proton exchange transporter CIC-5 and the phosphatidylinositol-4,5-biphosphate-5-phosphatase, respectively. Methods: Mutational analysis of CLCN5 gene from 4 unrelated patients diagnosed with Dent's disease and their relatives, 3 from Spain and 1 from Bolivia, was performed by PCR and automatic DNA sequencing. Results: In the current study, we report the identification of 4 mutations in CLCN5 of 1 family from Bolivia and 3 families from Spain. Two of the mutations are novel and consist of 1 nonsense mutation, Y502X, and 1 missense mutation, L225P, affecting CIC-5 α-helix F, one of the helices involved in formation of the chloride selectivity filter. Conclusions: Our results add to the expanding spectrum of mutations in CLCN5. This is the first report of a CLCN5 mutation in a Dent's disease patient of South American origin.