Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent'sJapan disease

被引:66
作者
Igarashi, T
Günther, W
Sekine, T
Inatomi, J
Shiraga, H
Takahashi, S
Suzuki, J
Tsuru, N
Yanagihara, T
Shimazu, M
Jentsch, TJ
Thakker, RV
机构
[1] Hammersmith Hosp, Imperial Coll, Sch Med, MRC,Clin Sci Ctr,Mol Endocrinol Grp, London W12 0NN, England
[2] Univ Tokyo, Fac Med, Dept Pediat, Tokyo 113, Japan
[3] Univ Hamburg, Ctr Mol Neurobiol, ZMNH, D-2000 Hamburg, Germany
[4] Tokyo Womens Med Sch, Tokyo, Japan
[5] Shizuoka Childrens Hosp, Dept Nephrol, Shizuoka, Japan
[6] Fukushima Med Coll, Dept Pediat, Fukushima 96012, Japan
[7] Chikushi Hosp, Fukuoka Med Sch, Dept Pediat, Fukuoka, Japan
[8] Yoshida Hosp, Dept Pediat, Niigata, Japan
[9] Mitsubishi Chem BCL, Tokyo, Japan
基金
英国医学研究理事会;
关键词
low-molecular-weight proteinuria; hypercalciuria; nephrocalcinosis; chloride channel gene;
D O I
10.1046/j.1523-1755.1998.00203.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background. 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 nephrocalcinosis, and this represents a variant of Dent's disease. Hitherto, 12 mutations of the X-linked renal specific chloride channel, CLCN5, have been reported in the Dent's(Japan) variant. To further identify such CLCN5 mutations and to define the structure-function relationships of this channel, we have investigated five unrelated, non-consanguinous Japanese families with this disorder. Methods. Leukocyte DNA from probands was used with CLCN5 primers for PCR amplification of the coding region, and the DNA sequences of the products determined. Functional studies were performed by expressing the mutants in Xenopus oocytes. Results. Five CLCN5 mutations consisting of two nonsense (R648X and R704X), two missense (S270R and L278F) and one acceptor splice site mutation (ag-->cg) in intron 4 were identified. The missense and splice site mutations represent novel abnormalities. Heterologous expression in Xenopus oocytes of wild-type and the missense mutants demonstrated that the mutations, which were translated, either abolished or markedly reduced chloride conductance. Conclusions. These results expand the spectrum of CLCN5 mutations associated with this renal disorder and provide insight into possible structure-function relationships. For example, both the missense mutations are located within a short putative loop between two transmembrane domains, and our results suggest that this region may have an important functional role in the regulation of channel activity.
引用
收藏
页码:1850 / 1856
页数:7
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