Zhang Zhen-Lin, He Jin-Wei, Zhang Hao, Hu Wei-Wei, Fu Wen-Zhen, Gu Jie-Mei, Yu Jin-Bo, Gao Gao, Hu Yun-Qiu, Li Miao, Liu Yu-Juan
The Department of Osteoporosis, Osteoporosis Research Unit, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 600 Yi-Shan Rd, Shanghai, 200233, People's Republic of China.
J Bone Miner Metab. 2009;27(4):444-51. doi: 10.1007/s00774-009-0051-0. Epub 2009 Mar 14.
Here we report the identification of two different mutations in chloride channel 7 gene in two unrelated patients with autosomal dominant osteopetrosis type II. We determined that one patient (a 32-year-old woman) carried a heterozygous gene for a R767W mutation in exon 24, and another patient (a 17-year-old boy) carried a heterozygous gene for a novel frameshift mutation (Glu798FS) in exon 25. Recent studies have reported loss-of-function mutations in the chloride channel 7 (CLCN7) gene as a cause of autosomal dominant osteopetrosis type II (ADO-II). The identification of gene mutations in Chinese with ADO has not been reported previously. In this study, we identified mutations of the CLCN7 gene in two unrelated Chinese families with ADO-II. Two probands with ADO-II were diagnosed based on their bone characteristics on X-rays and their laboratory results. All 25 exons of the CLCN7 gene, including the exon-intron boundaries, were sequenced. We found in family 1 that the proband (a 32-year-old woman) was heterozygous for a CLCN7 mutation. The nonsynonymous mutation consisted of a heterozygous C/T transition at codon 2327 in exon 24, which resulted in an arginine (CGG)-to tryptophan (TGG) substitution at position 767 (R767W). The same heterozygous mutation (C/T) was determined in her father and son, who were asymptomatic with normal skeleton radiography. In family 2, we found that the proband (a 17-year-old boy) carried a novel frameshift mutation (Glu798FS) resulting from a G insertion between codon 60 and codon 61 in exon 25. The heterozygous -/G insertion is predicted to elongate the peptide of CLCN7 by 120 amino acids after position 797 amino acids. Similarly, some individuals of this family carried the same heterozygous mutation, but they are all asymptomatic. Furthermore, the R767W and Glu798FS mutations were not found in 100 unrelated controls. Our present findings suggest that the novel Glu798FS mutation in exon 25 and R767W in exon 24 in the CLCN7 gene were responsible for ADO-II in these Chinese patients.
在此，我们报告在两名非亲缘关系的常染色体显性遗传II型骨硬化症患者中，发现了氯离子通道7基因的两种不同突变。我们确定一名患者（一名32岁女性）在第24外显子中携带R767W突变的杂合基因，另一名患者（一名17岁男孩）在第25外显子中携带一种新的移码突变（Glu798FS）的杂合基因。最近的研究报道，氯离子通道7（CLCN7）基因的功能丧失突变是常染色体显性遗传II型骨硬化症（ADO-II）的病因。此前尚未有关于中国ADO患者基因突变的报道。在本研究中，我们在两个非亲缘关系的中国ADO-II型家族中鉴定出CLCN7基因的突变。两名ADO-II型先证者根据其X线骨骼特征和实验室检查结果得以确诊。对CLCN7基因的所有25个外显子，包括外显子-内含子边界进行了测序。我们在家族1中发现，先证者（一名32岁女性）为CLCN7突变的杂合子。该非同义突变由第24外显子中密码子2327处的杂合C/T转换组成，导致第767位精氨酸（CGG）被色氨酸（TGG）取代（R767W）。在她的父亲和儿子中也检测到相同的杂合突变（C/T）,他们无症状，骨骼X线检查正常。在家族2中，我们发现先证者（一名17岁男孩）携带一种新的移码突变（Glu798FS），该突变由第25外显子中密码子60和密码子61之间插入一个G所致。预计该杂合-/G插入会使CLCN7的肽链在第797个氨基酸之后延长120个氨基酸。同样，该家族的一些个体也携带相同的杂合突变，但他们均无症状。此外，在100名非亲缘关系的对照中未发现R767W和Glu798FS突变。我们目前的研究结果表明，CLCN7基因第25外显子中的新突变Glu798FS和第24外显子中的R767W突变是这些中国患者ADO-II的病因。
