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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

Abstract

Summary

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.

Introduction

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.

Keywords

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

Notes

Acknowledgments

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)

References

  1. 1.
    Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A (2003) Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. J Bone Miner Res 18:1740–1747CrossRefPubMedGoogle Scholar
  2. 2.
    Okamoto F, Kajiya H, Fukushima H, Jimi E, Okabe K (2004) Prostaglandin E2 activates outwardly rectifying Cl(-) channels via a cAMP-dependent pathway and reduces cell motility in rat osteoclasts. Am J Physiol Cell Physiol 287:C114–C124CrossRefPubMedGoogle Scholar
  3. 3.
    Kelly ME, Dixon SJ, Sims SM (1994) Outwardly rectifying chloride current in rabbit osteoclasts is activated by hyposmotic stimulation. J Physiol 475:377–389CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, Phadke S, Lopez AG, Orchard P, Mihci E, Abinun M, Wright M, Vettenranta K, Bariae I, Melis D, Tezcan I, Baumann C, Locatelli F, Zecca M, Horwitz E, Mansour LS, Van Roij M, Vezzoni P, Villa A, Sobacchi C (2010) Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Hum Mutat 31:E1071–E1080CrossRefPubMedGoogle Scholar
  5. 5.
    Waguespack SG, Koller DL, White KE, Fishburn T, Carn G, Buckwalter KA, Johnson M, Kocisko M, Evans WE, Foroud T, Econs MJ (2003) Chloride channel 7 (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II. J Bone Miner Res 18:1513–1518CrossRefPubMedGoogle Scholar
  6. 6.
    Faundez V, Hartzell HC (2004) Intracellular chloride channels: determinants of function in the endosomal pathway. Sci STKE e8Google Scholar
  7. 7.
    Stark Z, Savarirayan R (2009) Osteopetrosis. Orphanet J Rare Dis 4:5CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Whyte MP, Kempa LG, McAlister WH, Zhang F, Mumm S, Wenkert D (2010) Elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish Albers-Schonberg disease (chloride channel 7 deficiency osteopetrosis) among the sclerosing bone disorders. J Bone Miner Res 25:2515–2526CrossRefPubMedGoogle Scholar
  9. 9.
    Alatalo SL, Ivaska KK, Waguespack SG, Econs MJ, Vaananen HK, Halleen JM (2004) Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis). Clin Chem 50:883–890CrossRefPubMedGoogle Scholar
  10. 10.
    Henriksen K, Gram J, Schaller S, Dahl BH, Dziegiel MH, Bollerslev J, Karsdal MA (2004) Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing autosomal dominant osteopetrosis type II. Am J Pathol 164:1537–1545CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Campos-Xavier AB, Casanova JL, Doumaz Y, Feingold J, Munnich A, Cormier-Daire V (2005) Intrafamilial phenotypic variability of osteopetrosis due to chloride channel 7 (CLCN7) mutations. Am J Med Genet A 133A:216–218CrossRefPubMedGoogle Scholar
  12. 12.
    Cleiren E, Benichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, Beaverson K, Aledo A, Whyte MP, Yoneyama T, DeVernejoul MC, Van Hul W (2001) Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 10:2861–2867CrossRefPubMedGoogle Scholar
  13. 13.
    Letizia C, Taranta A, Migliaccio S, Caliumi C, Diacinti D, Delfini E, D’Erasmo E, Iacobini M, Roggini M, Albagha OM, Ralston SH, Teti A (2004) Type II benign osteopetrosis (Albers-Schonberg disease) caused by a novel mutation in CLCN7 presenting with unusual clinical manifestations. Calcif Tissue Int 74:42–46CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang ZL, He JW, Zhang H, Hu WW, Fu WZ, Gu JM, Yu JB, Gao G, Hu YQ, Li M, Liu YJ (2009) Identification of the CLCN7 gene mutations in two Chinese families with autosomal dominant osteopetrosis (type II). J Bone Miner Metab 27:444–451CrossRefPubMedGoogle Scholar
  15. 15.
    Wang C, Zhang H, He JW, Gu JM, Hu WW, Hu YQ, Li M, Liu YJ, Fu WZ, Yue H, Ke YH, Zhang ZL (2012) The virulence gene and clinical phenotypes of osteopetrosis in the Chinese population: six novel mutations of the CLCN7 gene in twelve osteopetrosis families. J Bone Miner Metab 30:338–348CrossRefPubMedGoogle Scholar
  16. 16.
    Zheng H, Zhang Z, He JW, Fu WZ, Wang C, Zhang ZL (2014) Identification of two novel CLCN7 gene mutations in three Chinese families with autosomal dominant osteopetrosis type II. Joint Bone Spine 81:188–189CrossRefPubMedGoogle Scholar
  17. 17.
    Rashid BM, Rashid NG, Schulz A, Lahr G, Nore BF (2013) A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series. J Med Case Rep 7:7CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Xue Y, Wang W, Mao T, Duan X (2012) Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia. J Craniomaxillofac Surg 40:416–420CrossRefPubMedGoogle Scholar
  19. 19.
    Schmidt-Rose T, Jentsch TJ (1997) Transmembrane topology of a CLC chloride channel. Proc Natl Acad Sci U S A 94:7633–7638CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Campos-Xavier AB, Saraiva JM, Ribeiro LM, Munnich A, Cormier-Daire V (2003) Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis. Hum Genet 112:186–189PubMedGoogle Scholar
  21. 21.
    Waguespack SG, Hui SL, Dimeglio LA, Econs MJ (2007) Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation. J Clin Endocrinol Metab 92:771–778CrossRefPubMedGoogle Scholar
  22. 22.
    Mitri Z, Tangpricha V (2012) Osteopetrosis, hypophosphatemia, and phosphaturia in a young man: a case presentation and differential diagnosis. Case Rep Endocrinol 238364Google Scholar
  23. 23.
    Chu K, Koller DL, Snyder R, Fishburn T, Lai D, Waguespack SG, Foroud T, Econs MJ (2005) Analysis of variation in expression of autosomal dominant osteopetrosis type 2: searching for modifier genes. Bone 37:655–661CrossRefPubMedGoogle Scholar

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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