MUTATIONS OF CLCN5 IN JAPANESE CHILDREN WITH IDIOPATHIC LOW-MOLECULAR-WEIGHT PROTEINURIA, HYPERCALCIURIA AND NEPHROCALCINOSIS

The annual urinary screening of Japanese children above three years of age has identified a progressive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcino sis. The disorder has been observed in over 60 patients and has a fami lial predisposition. Mutations of a renal chloride channel gene, CLCN5 ; have been reported in four such families, and we have undertaken stu dies in additional patients from 10 unrelated, non-consanguineous Japa nese families to further characterize such CLCN5 mutations and to asce rtain their prevalence. CLCN5 abnormalities were identified in 7 of th e 10 unrelated patients and consisted of 5 mutations (2 nonsense, 1 fr ameshift and 2 missense), 1 deletion and 1 silent polymorphism. A clus tering of these mutations in CLCN5 exons 8 and 10 was observed. Over 8 0% of the CLCN5 mutations could be readily detected by single stranded conformational polymorphism (SSCP) analysis, thereby providing a usef ul mutation screening method. Our results, which indicate that over 70 % of Japanese patients with this renal tubulopathy have CLCN5 mutation s, will help in the genetic and clinical evaluation of children at ris k from this disorder.