Morimoto T, Uchida S, Sakamoto H, Kondo Y, Hanamizu H, Fukui M, Tomino Y, Nagano N, Sasaki S, Marumo F
Second Department of Internal Medicine, Tokyo Medical and Dental University, School of Medicine, Japan.
J Am Soc Nephrol. 1998 May;9(5):811-8. doi: 10.1681/ASN.V95811.
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) mutation were found in three patients in the two families having only LMWP. One genomic deletion including exons 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 mutations of the exons and exon-intron boundaries in the CLCN5 gene were 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.
CLCN5基因突变已在三种高钙尿性肾结石疾病中得到证实，即丹特病、X连锁隐性肾结石病和X连锁隐性低磷血症佝偻病。最近，有报道称，一些日本低分子量蛋白尿（LMWP）患儿出现了与英国家庭中丹特病患者相似的症状，他们的CLCN5基因也存在突变。本研究对五个无亲缘关系的日本LMWP家庭进行了检查，其中两个家庭除LMWP外没有任何其他症状，另外三个家庭除LMWP外还有一些其他症状，即高钙尿症、氨基酸尿症、低磷血症和佝偻病。在仅患有LMWP的两个家庭中的三名患者中发现了一个无义突变（E118X）和一个错义突变（W22G）。在一名低磷血症佝偻病患者中发现了CLCN5基因中一个包括外显子5至8的基因组缺失，在一名患有LMWP和轻度高钙尿症的患者中发现了一个无义突变（R347X）。在一名患有LMWP、氨基酸尿症和低钾血症的患者中未发现CLCN5基因外显子及外显子-内含子边界的突变。除了这些无义突变和缺失突变预计会导致氯离子通道功能丧失外，在非洲爪蟾卵母细胞表达系统中证实了错义突变W22G也会导致功能丧失。这些结果明确了CLCN5基因中的四个新突变，此外还表明CLCN5功能丧失突变在疾病早期不一定会导致高钙尿症和肾钙质沉着症，并且LMWP是CLC-5氯离子通道疾病的早期和重要表现。
