Fisher S E, van Bakel I, Lloyd S E, Pearce S H, Thakker R V, Craig I W
Biochemistry Department, University of Oxford, United Kingdom.
Genomics. 1995 Oct 10;29(3):598-606. doi: 10.1006/geno.1995.9960.
Dent disease, an X-linked familial renal tubular disorder, is a form of Fanconi syndrome associated with proteinuria, hypercalciuria, nephrocalcinosis, kidney stones, and eventual renal failure. We have previously used positional cloning to identify the 3' part of a novel kidney-specific gene (initially termed hClC-K2, but now referred to as CLCN5), which is deleted in patients from one pedigree segregating Dent disease. Mutations that disrupt this gene have been identified in other patients with this disorder. Here we describe the isolation and characterization of the complete open reading frame of the human CLCN5 gene, which is predicted to encode a protein of 746 amino acids, with significant homology to all known members of the ClC family of voltage-gated chloride channels. CLCN5 belongs to a distinct branch of this family, which also includes the recently identified genes CLCN3 and CLCN4. We have shown that the coding region of CLCN5 is organized into 12 exons, spanning 25-30 kb of genomic DNA, and have determined the sequence of each exon-intron boundary. The elucidation of the coding sequence and exon-intron organization of CLCN5 will both expedite the evaluation of structure/function relationships of these ion channels and facilitate the screening of other patients with renal tubular dysfunction for mutations at this locus.
丹特病是一种X连锁的家族性肾小管疾病，是范科尼综合征的一种形式，与蛋白尿、高钙尿症、肾钙质沉着症、肾结石以及最终的肾衰竭相关。我们之前利用定位克隆技术鉴定了一个新的肾脏特异性基因的3'端部分（最初称为hClC-K2，但现在称为CLCN5），在一个患丹特病的家系中，该基因在患者体内缺失。在患有这种疾病的其他患者中也发现了破坏该基因的突变。在此，我们描述了人类CLCN5基因完整开放阅读框的分离和特征，该基因预计编码一个746个氨基酸的蛋白质，与电压门控氯离子通道ClC家族的所有已知成员具有显著同源性。CLCN5属于该家族的一个独特分支，该分支还包括最近鉴定的基因CLCN3和CLCN4。我们已经表明，CLCN5的编码区由12个外显子组成，跨越25 - 30 kb的基因组DNA，并确定了每个外显子-内含子边界的序列。CLCN5编码序列和外显子-内含子结构的阐明将加快对这些离子通道结构/功能关系的评估，并有助于筛查其他肾小管功能障碍患者在该位点的突变。
