IDIOPATHIC LOW-MOLECULAR-WEIGHT PROTEINURIA ASSOCIATED WITH HYPERCALCIURIC NEPHROCALCINOSIS IN JAPANESE CHILDREN IS DUE TO MUTATIONS OF THERENAL CHLORIDE CHANNEL (CLCN5)

The annual urinary screening of Japanese children above 5 yr of age ha s identified a progressive proximal renal tubular disorder characteriz ed by low molecular weight proteinuria, hypercalciuria, and nephrocalc inosis. The disorder, which has a familial predisposition and occurs p redominantly in males, has similarities to three X-linked proximal ren al tubular disorders that are due to mutations in the renal chloride c hannel gene, CLCN5. We have investigated four unrelated Japanese kindr eds with this tubulopathy and have identified four different CLCN5 mut ations (two nonsense, one missense, and one frameshift). These are pre dicted to lead to a loss of chloride channel function, and heterologou s expression of the missense CLCN5 mutation in Xenopus oocytes demonst rated a 70% reduction in channel activity when compared with the wild- type. In addition, single-stranded conformation polymorphism (SSCP) an alysis was found to be a sensitive and specific mutational screening m ethod that detected > 75% of CLCN5 mutations. Thus, the results of our study expand the spectrum of clinical phenotypes associated with CLCN 5 mutations to include this proximal renal tubular disorder of Japanes e children. In addition, the mutational screening of CLCN5 by SSCP wil l help to supplement the clinical evaluation of the annual urinary scr eening program for this disorder.