Dent's disease: identification of a novel mutation in the renal chloride channel CLCN5.

Objective: Dent’s disease is an X-linked renal tubular disorder characterized by low molecular-weight proteinuria, hypercalciuria, nephrolithiasis and progressive renal failure. There is a significant variability in the severity of this disease among patients, moreover, other renal proximal tubular defects may also occur. This leads to an overlap with other tubular disorders especially in an early stage of the disease making an early diagnosis often difficult. Dent’s disease is caused by a mutation in the renal-specific chloride channel gene CLCN5 located on chromosome Xp11.22. Until now, 49 hCLC-5 mutations associated with Dent’s disease have been published. We report a 36-year-old patient with progressive renal insufficiency and symptoms of a tubular disorder. As a child he showed features of a Fanconi-syndrome and X-linked hypophosphatemic rickets. In 1994 Dent’s disease was already suspected but it was only with genetic analysis that a new mutation in the CLCN5 gene was revealed and Dent’s disease finally diagnosed. Methods: Genomic DNA was isolated from peripheral blood and the 11 coding exons of CLCN5 were analyzed by RT-PCR. PCR products were sequenced by use of an ABI 377 automatic sequencer. Primer pairs were placed in the intronic sequences flanking respective exons and functionalty of primers was ensured by amplification of all coding exons of CLCN5 from genomic DNA from healthy controls. Results: RT-PCR amplification and sequencing of exons 2–12 of the CLCN5 gene of this patient revealed a 658 bp deletion including the complete sequence of exon 5 (123 bp) and 532 bp of the upstream intron 4 and 3 bp of the downstream intron 5. This deleted sequence was replaced by a 49 bp insertion which turned out to be partially (34 5 bp) a reverse strand of the deleted sequence. Conclusions: The present case underlines the clinical variety of symptoms found in Dent’s disease. We hypothesize that this disorder is underdiagnosed especially in young male patients suffering from renal insufficiency and propose that genetic analysis for this disorder should be included in patients when a tubular disorder seems likely. P13.02