Osteoporosis International

, Volume 27, Issue 3, pp 1047–1055 | Cite as

Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADO-II) and intermediate autosomal recessive osteopetrosis (IARO) in Chinese patients

  • Q. Pang
  • Y. Chi
  • Z. Zhao
  • X. Xing
  • M. Li
  • O. Wang
  • Y. Jiang
  • R. Liao
  • Y. Sun
  • J. Dong
  • W. XiaEmail author
Original Article



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.


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.


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.


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).


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.


Autosomal dominant osteopetrosis type II CLCN7 Clinical manifestation Intermediate autosomal recessive osteopetrosis Mutation Phenotype 



We appreciate the patients and their family members for their participating in this study.

This study was supported by the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (No.2008ZX09312-016), the National Natural Science Foundation of China (No. 81070687, 81170805), the National Key Program of Clinical Science (No. WBYZ2011-873), the Beijing Natural Science Foundation (No. 7121012), and the Scientific Research Foundation of Beijing Medical Development (No. 2007-3029).

Conflicts of interest

Qianqian Pang, Yue Chi, Zhen Zhao, Xiaoping Xing, Mei Li, Ou Wang, Yan Jiang, Ruoxi Liao, Yue Sun, Jin Dong, and Weibo Xia declare that they have no conflict of interest.

Supplementary material

198_2015_3320_Fig5_ESM.gif (82 kb)
Figure S1

Protein sequence alignment of the flanking regions of the mutations among different species. These missense mutations all occur at highly conserved positions, as shown by a comparison of the protein sequence from seven or eight vertebrates (From BLAST®, NCBI database). The mutations found in this study and the positions of amino acid were marked by blue rectangle. (GIF 81 kb)

198_2015_3320_MOESM1_ESM.tif (5.1 mb)
High resolution (TIFF 5271 kb)
198_2015_3320_MOESM2_ESM.docx (21 kb)
Table S1 (DOCX 20 kb)
198_2015_3320_MOESM3_ESM.docx (26 kb)
Table S2 (DOCX 25 kb)


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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2015

Authors and Affiliations

  • Q. Pang
    • 1
    • 2
  • Y. Chi
    • 1
  • Z. Zhao
    • 1
    • 3
  • X. Xing
    • 1
  • M. Li
    • 1
  • O. Wang
    • 1
  • Y. Jiang
    • 1
  • R. Liao
    • 1
  • Y. Sun
    • 1
  • J. Dong
    • 2
  • W. Xia
    • 1
    Email author
  1. 1.Department of Endocrinology, Key Laboratory of Endocrinology, The Ministry of Health, Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingChina
  2. 2.Department of EndocrinologyThe First affiliated Hospital of Shanxi Medical UniversityTaiyuanChina
  3. 3.Department of GeriatricsBeijing Friendship Hospital affiliated to Capital Medical UniversityBeijingChina

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