MUTATIONS IN THE CLCN5 GENE IN JAPANESE PATIENTS WITH FAMILIAL IDIOPATHIC LOW-MOLECULAR-WEIGHT PROTEINURIA

Familial idiopathic low-molecular-weight proteinuria (FILMWP) is a ren al proximal tubulopathy that occurs predominantly in males. FILMWP is characterized by mild proteinuria consisting of low-molecular-weight p roteinuria, aminoaciduria and relatively conserved renal function, but without rickets. To determine whether FILMWP is related to the CLCN5 gene, which is responsible for Dent's disease and two related disorder s, we analyzed the CLCN5 gene from four Japanese families with FILMWP. We identified two novel mutations: one was a single base insertion al codon 520 serine in exon 10 and the other was a single base deletion at codon 403 tyrosine in exon 8. These mutations caused a shift in the reading frame, resulting in synthesis of truncated CLC5 proteins that lacked 220 (29%) and 314 (42%) amino acids, respectively. These mutat ions were demonstrated to cosegregate with the disease in two families , respectively. We conclude that the CLCN5 gene is responsible for thi s proximal renal tubulopathy in some Japanese families and that FILMWP is possibly a variant of Dent's disease.