Phenotypic and genetic heterogeneity in Dent's disease - the results of an Italian collaborative study

Abstract BACKGROUND: Dent's disease is an inherited tubulopathy caused by CLCN5 gene mutations. While a typical phenotype characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and progressive renal failure in various combinations often enables a clinical diagnosis, less severe sub-clinical cases may go under-diagnosed. METHODS: By single-strand conformation polymorphism analysis and direct sequencing, we screened 40 male patients from 40 unrelated families for CLCN5 gene mutations. Twenty-four of these patients had the prominent features of Dent's disease, including LMW proteinuria, hypercalciuria and nephrocalcinosis. RESULTS: We identified 24 mutations in the CLCN5 gene in 21/24 patients with a typical phenotype and in 3/16 patients with a partial clinical picture of Dent's disease. Overall, 10 novel CLCN5 mutations were identified (E6fsX11, W58fsX97, 267 del E, Y272C, N340K, F444fsX448, W547X, Q600X, IVS3 +2 G>C and IVS3 -1 G>A), extending the number of mutations identified so far from 75 to 85. The CLCN5 coding sequence was normal in three patients. In the group with an incomplete Dent's disease phenotype, we detected two intronic mutations and one silent substitution leading to the up regulation of an alternatively spliced isoform. CONCLUSIONS: Our data confirm the genetic heterogeneity of Dent's disease. In most classic cases, the clinical diagnosis is confirmed by genetic tests.