title: Two novel mutations of CLCN7 gene in Chinese families with autosomal dominant osteopetrosis (type II).
abstract: Autosomal dominant osteopetrosis type II (ADO-II) is a heritable bone disorder characterized by osteosclerosis, predominantly involving the spine (vertebral end-plate thickening, or rugger-jersey spine), the pelvis ("bone-within-bone" structures) and the skull base. Chloride channel 7 (CLCN7) has been reported to be the causative gene. In this study, we aimed to identify the pathogenic mutation in four Chinese families with ADO-II. All 25 exons of the CLCN7 gene, including the exon-intron boundaries, were amplified and sequenced directly in four probands from the Chinese families with ADO-II. The mutation site was then identified in other family members and 250 healthy controls. In family 1, a known missense mutation c.296A>G in exon 4 of CLCN7 was identified in the proband, resulting in a tyrosine (UAU) to cysteine (UGU) substitution at p.99 (Y99C); the mutation was also identified in his affected father. In family 2, a novel missense mutation c.865G>C in exon 10 was identified in the proband, resulting in a valine (GUC) to leucine (CUC) substitution at p.289 (V289L); the mutation was also identified in her healthy mother and sister. In family 3, a novel missense mutation c.1625C>T in exon 17 of CLCN7 was identified in the proband, resulting in an alanine (GCG) to valine (GUG) substitution at p.542 (A542V); the mutation was also identified in her father. In family 4, a hot spot, R767W (c.2299C>T, CGG>TGG), in exon 24 was found in the proband which once again proved the susceptibility of the site or the similar genetic background in different races. Moreover, two novel mutations, V289L and A542V, occurred at a highly conserved position, found by a comparison of the protein sequences from eight vertebrates, and were predicted to have a pathogenic effect by PolyPhen-2 software, which showed "probably damaging" with a score of approximately 1. These mutation sites were not identified in 250 healthy controls. Our present findings suggest that the novel missense mutations V289L and A542V in the CLCN7 gene were responsible for ADO-II in the two Chinese families.
authors.affiliation: Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Rd, Shanghai, 200233, People's Republic of China.|Shanghai Key Clinical Center for Metabolic Disease, Shanghai, 200233, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Rd, Shanghai, 200233, People's Republic of China.|Shanghai Key Clinical Center for Metabolic Disease, Shanghai, 200233, People's Republic of China.
authors.forename: Chong
authors.initials: C
authors.lastname: Shao
authors.affiliation: Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Rd, Shanghai, 200233, People's Republic of China.|Shanghai Key Clinical Center for Metabolic Disease, Shanghai, 200233, People's Republic of China.|Department of Endocrinology, Yueqing Hospital Affiliated to Wenzhou Medical University, Yueqing, Zhejiang, 325600, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Rd, Shanghai, 200233, People's Republic of China.|Shanghai Key Clinical Center for Metabolic Disease, Shanghai, 200233, People's Republic of China.
authors.forename: Jin-Wei
authors.initials: JW
authors.lastname: He
authors.affiliation: Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Rd, Shanghai, 200233, People's Republic of China.|Shanghai Key Clinical Center for Metabolic Disease, Shanghai, 200233, People's Republic of China.
authors.forename: Wen-Zhen
authors.initials: WZ
authors.lastname: Fu
authors.affiliation: Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Rd, Shanghai, 200233, People's Republic of China.|Shanghai Key Clinical Center for Metabolic Disease, Shanghai, 200233, People's Republic of China.
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Rd, Shanghai, 200233, People's Republic of China. zzl2002@medmail.com.cn.|Shanghai Key Clinical Center for Metabolic Disease, Shanghai, 200233, People's Republic of China. zzl2002@medmail.com.cn.
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Zhang
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002675:Child, Preschool; D002681:China; D018118:Chloride Channels / Q000235:genetics*; D005091:Exons; D005190:Family; D005260:Female; D006801:Humans; D007438:Introns; D008297:Male; D020125:Mutation, Missense; D010022:Osteopetrosis / Q000235:genetics*; D010375:Pedigree
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels
keywords: Autosomal dominant osteopetrosis type II; CLCN7; Mutation