Molecular and clinical studies of Dent's disease in Japan: Biochemical examination and renal ultrasonography do not predict carrier state

Background: Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight-proteinuria, hypercalciuria, nephrolithiasis and renal failure. The disease is due to inactivation of a renal chloride channel gene, CLCN5. We have investigated 3 unrelated Japanese families for CLCN5 mutations and assessed the carrier mothers biochemically and ultrasonogaraphically to ascertain whether these clinical examinations can predict the carrier state of the disease. Material and methods: Twelve members from these families were studied biochemically and ultrasonographically. Leukocyte DNA from probands was used with CLCN5-specific primers for PCR amplification of the coding region and exon-intron boundaries, and the DNA sequences of the products determined to identify abnormalities in the gene. Results: Three novel CLCN5 mutations consisting of a single base "A" insertion between nucleotides 590 and 591, a nonsense mutation (R28X) and a missense mutation (G506R) were exhibited. Hypophosphatemia was detected in 2 patients, β₂-microglobulinuria, α₁-microglobulinuria, and hyperretinol binding proteinuria in 6 patients, hypercalciuria in 5 patients, decreased urine osmolality in 3 patients, and nephrocalcinosis or nephrolithiasis in 4 patients. Biochemical analysis of the urine and the renal ultrasonography in each carrier mother were completely normal. Conclusions: Neither urinary low-molecular-weight-proteins, urinary calcium to creatinine ratio, nor renal ultrasonography was predictive of carrier state in the 3 families with this disease, although each carrier mother had CLCN5 mutation. Hypophosphatemia and decreased urine osmolality might be a hint to suspect the carrier state of Dent's disease, although these findings are not found frequently.