Dent's disease, or nephropathy related to CLCN5 mutations: a new entity.

In 1994, a British group reported a syndrome of tubular proteinuria in chil dren, sometimes with Fanconi's syndrome and often with hypercalciuria and/o r rickets. They called this entity Dent's disease to acknowledge the descri ption 30 years earlier of two similar cases by Dent. In adulthood most affe cted patients were males and manifestations were nephrocalcinosis, nephroli thiasis, and progressive renal failure. Data were consistent with X-linked dominant transmission with marked male predominance of the most serious man ifestations. In recent years, three other clinical disorders of X-linked hy percalciuric nephrolithiasis have been reported, namely X-linked recessive nephrolithiasis with renal failure (XRN) in the United States, X-linked rec essive hypophosphatemic rickets (XLHR) in Italy and France, and familial id iopathic low-molecular-weight proteinuria (FILMWP) in Japan. Despite some d ifferences, these syndromes share many phenotypic features with Dent's synd rome. Molecular biology studies have established that all four syndromes ar e due to mutations affecting a single gene, CLCN5, recently identified usin g a positional cloning approach. No genotype-syndrome correlations have bee n found, suggesting that all four syndromes are facets of a single entity, which could be called Dent's disease. The putative function of the protein encoded by CLCN5 (CLC5) is surprising: sequence homology and functional stu dies indicate that CLC5 may be a new member of the CLC family of voltage-ga ted chloride channels. Recent studies have elucidated the mechanisms of the tubular proteinuria, but the underpinnings of the other phenotype abnormal ities remain unknown. The treatment of Dent's disease still relies solely o n symptomatic measures.