Molecular and functional analysis of CIC-5 in idiopathic low-molecular-weight proteinuria

1999 Fiscal Year Final Research Report Summary

• Project/Area Number: 10670703
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: TOHOKU UNIVERSITY
• Principal Investigator: AIBA Satoru Tohoku University Hospital, Research Associate, 医学部・附属病院, 助手 (20261612)
• Co-Investigator(Kenkyū-buntansha): TANAKA Takashi Tohoku University Hospital, Research Associate, 医学部・附属病院, 助手 (10292335) ; NAGANO Chiyoko Tohoku University Hospital, Research Associate, 医学部・附属病院, 助手 (70261633) ; KONDO Yoshiaki Graduate School of Medicine, Tohoku University, Assistant Professor, 大学院・医学系研究科, 講師 (00221250)
• Project Period (FY): 1998 – 1999
• Keywords: low-molecular-weight protein / renal tubulopathy / chloride ion / genetic disorders / voided tubule cells / cell culture

Research Abstract

Mutations in the CLCN5 gene have been demonstrated in three disorders of hypercalciuric nephrolithiasis, i.e., Dent's disease, X-linked recessive nephrolithiasis, and X-linked recessive hypophosphatemic rickets. Recently, a number of Japanese children with low-molecular-weight proteinuria (LMWP) showing symptoms similar to those shown by patients with Dent's disease in British families have also been reported to have mutations in the CLCN5 gene. The present study examines five unrelated Japanese families with LMWP, two of which lacked any signs other than LMWP, and three of which had several signs other than LMWP, i.e., hypercalciuria, aminoaciduria, hypophosphatemia, and rickets. One nonsense (E118X) and one missense (W22G) mutations were found in three patients in the two families having only LMWP. One genomic deletion including exon 5 to 8 in the CLCN5 gene was found in a patient with hypophosphatemic rickets, and a nonsense mutation (R347X) was found in one patient with LMWP and slight hypercalciuria. No mutation of the exons and exon-intron boundaries in the CLCN5 gene was found in one patient with LMWP, aminoaciduria, and hypokalemia. In addition to the predicted loss of chloride channel function in these nonsense and deletion mutations, the loss of function in the missense mutation W22G was confirmed in the Xenopus oocyte expression system. These results clarified four novel mutations in the CLCN5 genes and additionally suggested that the loss-of-function mutation of the CLCN5 does not necessarily lead to hypercalciuria and nephrocalcinosis in the early stage of the disease, and that LMWP is an early and essential manifestation of disorders of the CLC-5 chloride channel.