title: Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADO-II) and intermediate autosomal recessive osteopetrosis (IARO) in Chinese patients.
abstract: CONCLUSIONS
  Osteopetrosis is a group of genetic bone disorders. Mutations in the chloride channel 7 gene (CLCN7) lead to chloride channel defect, which results in autosomal dominant osteopetrosis type II (ADO-II), autosomal recessive osteopetrosis (ARO), and intermediate autosomal recessive osteopetrosis (IARO). In the present study, we identified seven novel mutations of the CLCN7 gene and reported the first case of IARO with compound heterozygous mutation in Chinese population.
  
  
  BACKGROUND
  Osteopetrosis is a heritable bone disorder due to the deficiency of or function defect in osteoclasts. Mutations in the CLCN7 lead to chloride channel defects, which result in osteopetrosis with diverse severity ranging from asymptomatic or relatively mild symptoms in ADO-II to the very severe phenotype in ARO. Heterozygous mutations in CLCN7 are associated to ADO-II, while homozygous and compound heterozygous mutations in CLCN7 may result in ARO and IARO. To date, a total of 24 mutations in CLCN7 were identified in ADO-II, and only 3 mutations were identified in IARO. In the present study, we reported seven unrelated ADO-II patients and one IARO patient from Chinese population and elucidated the characteristics of CLCN7 gene mutations in these patients.
  
  
  METHODS
  All 25 CLCN7 exons and exon-intron boundaries from genomic DNA were amplified and sequenced in eight affected individuals suffering from ADO-II/IARO. The clinical, biochemical, and radiographic analysis were evaluated to compare the differences between ADO-II and IARO both in genotype and phenotype.
  
  
  RESULTS
  The results showed that there were seven novel CLCN7 mutations identified in these ADO-II/IARO patients, including six heterozygous missense mutations (p.L224R, p.S290Y, p.R326G, p.G347R, p.S473N, and p.L564P) and a novel splice mutation (p.K691FS).
  
  
  CONCLUSIONS
  The compound heterozygous mutations (p.L224R and p.K691FS) were firstly observed in one IARO patient. The present study would enrich the database of CLCN7 mutations and improve our understanding of this heritable bone disorder.
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.|Department of Endocrinology, The First affiliated Hospital of Shanxi Medical University, Taiyuan, 030001, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Pang
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chi
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.|Department of Geriatrics, Beijing Friendship Hospital affiliated to Capital Medical University, Beijing, 100050, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
authors.forename: X
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
authors.forename: O
authors.initials: O
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
authors.forename: R
authors.initials: R
authors.lastname: Liao
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Endocrinology, The First affiliated Hospital of Shanxi Medical University, Taiyuan, 030001, China.
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China. xiaweibo@medmail.com.cn.
authors.forename: W
authors.initials: W
authors.lastname: Xia
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D015519:Bone Density / Q000235:genetics / Q000502:physiology; D002648:Child; D018118:Chloride Channels / Q000235:genetics*; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae / Q000503:physiopathology; D008297:Male; D020125:Mutation, Missense; D010022:Osteopetrosis / Q000151:congenital / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D055815:Young Adult
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels
keywords: Autosomal dominant osteopetrosis type II; CLCN7; Clinical manifestation; Intermediate autosomal recessive osteopetrosis; Mutation; Phenotype