Journal of Bone and Mineral Metabolism

, Volume 30, Issue 3, pp 338–348 | Cite as

The virulence gene and clinical phenotypes of osteopetrosis in the Chinese population: six novel mutations of the CLCN7 gene in twelve osteopetrosis families

  • Chun Wang
  • Hao Zhang
  • Jin-Wei He
  • Jie-Mei Gu
  • Wei-Wei Hu
  • Yun-Qiu Hu
  • Miao Li
  • Yu-Juan Liu
  • Wen-Zhen Fu
  • Hua Yue
  • Yao-Hua Ke
  • Zhen-Lin ZhangEmail author
Original Article


Osteopetrosis is a heritable bone disorder resulting from a deficiency of or a functional defect in osteoclasts. We aimed to characterize the molecular defects and clinical manifestations in Chinese patients with osteopetrosis by studying 12 unrelated osteopetrosis families. The entire coding region and adjacent splice sites of the CLCN7, TCIRG1, LRP5 and SOST genes were amplified and directly sequenced. X-rays of hip and lumbar spine, bone mineral density and bone turnover markers were examined simultaneously. Family history and fracture history were collected using a questionnaire. Among 12 unrelated families, 10 families were diagnosed with autosomal dominant osteopetrosis type II (ADOII) with 10 probands and 3 affected subjects. Two individuals in the other two families were diagnosed with uncategorized osteopetrosis because no mutations were detected in any of the four studied genes. Eight mutations, including two reported mutations (R767W and E798FS) and six novel mutations (E313K, A316G, R743W, G741R, W127G and S290F), were detected in the CLCN7 gene from 12 living ADOII patients. Among them, R767W and R743W mutations were two common mutations that were each found in 20% of 10 ADOII probands. In CLCN7-related ADOII patients, long bone fractures and elevated serum CK level were two major clinical phenotypes, especially in patients younger than 18 years. Further functional studies of the above eight mutations in the CLCN7 gene are needed in the future.


Osteopetrosis CLCN7 Mutation Phenotype 



We thank the patients and their family members for their invaluable cooperation. The study was supported by the National Natural Science Foundation of China (NSFC) (No. 30771019, 30800387, 81070692); Program of Shanghai Chief Scientist (Project No. 08XD1403000) and STCSM10DZ1950100; Shanghai Science and Technology Development Fund (Project No. 08411963100 and 11ZR1427300); Shanghai Rising-Star program (11QA1404900).

Conflict of interest

The authors have no conflicts of interest.


  1. 1.
    Stark Z, Savarirayan R (2009) Osteopetrosis. Orphanet J Rare Dis 4:5PubMedCrossRefGoogle Scholar
  2. 2.
    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 10:2861–2867PubMedCrossRefGoogle Scholar
  3. 3.
    Tolar J, Teitelbaum SL, Orchard PJ (2004) Osteopetrosis. N Engl J Med 351:2839–2849PubMedCrossRefGoogle Scholar
  4. 4.
    Henriksen K, Gram J, Hoegh-Andersen P, Jemtland R, Ueland T, Dziegiel MH, Schaller S, Bollerslev J, Karsdal MA (2005) Osteoclasts from patients with autosomal dominant osteopetrosis type I caused by a T253I mutation in low-density lipoprotein receptor-related protein 5 are normal in vitro, but have decreased resorption capacity in vivo. Am J Pathol 167:1341–1348PubMedCrossRefGoogle Scholar
  5. 5.
    Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Benichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W (2003) Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 72:763–771PubMedCrossRefGoogle Scholar
  6. 6.
    Del Fattore A, Cappariello A, Teti A (2008) Genetics, pathogenesis and complications of osteopetrosis. Bone 42:19–29PubMedCrossRefGoogle Scholar
  7. 7.
    Chalhoub N, Benachenhou N, Rajapurohitam V, Pata M, Ferron M, Frattini A, Villa A, Vacher J (2003) Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med 9:399–406PubMedCrossRefGoogle Scholar
  8. 8.
    Pangrazio A, Poliani PL, Megarbane A, Lefranc G, Lanino E, Di Rocco M, Rucci F, Lucchini F, Ravanini M, Facchetti F, Abinun M, Vezzoni P, Villa A, Frattini A (2006) Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement. J Bone Miner Res 21:1098–1105PubMedCrossRefGoogle Scholar
  9. 9.
    Shin YJ (2004) Chloride channel CICN7 mutations in a Korean patient with infantile malignant osteopetrosis initially presenting with neonatal thrombocytopenia. J Perinatol 24:312–314PubMedCrossRefGoogle Scholar
  10. 10.
    Aramaki S, Yoshida I, Yoshino M, Kondo M, Sato Y, Noda K, Jo R, Okue A, Sai N, Yamashita F (1993) Carbonic anhydrase II deficiency in three unrelated Japanese patients. J Inherit Metab Dis 16:982–990PubMedCrossRefGoogle Scholar
  11. 11.
    Lam CW, Tong SF, Wong K, Luo YF, Tang HY, Ha SY, Chan MH (2007) DNA-based diagnosis of malignant osteopetrosis by whole-genome scan using a single-nucleotide polymorphism microarray: standardization of molecular investigations of genetic diseases due to consanguinity. J Hum Genet 52:98–101PubMedCrossRefGoogle Scholar
  12. 12.
    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 27:444–451PubMedCrossRefGoogle Scholar
  13. 13.
    Taranta A, Migliaccio S, Recchia I, Caniglia M, Luciani M, De Rossi G, Dionisi-Vici C, Pinto RM, Francalanci P, Boldrini R, Lanino E, Dini G, Morreale G, Ralston SH, Villa A, Vezzoni P, Del Principe D, Cassiani F, Palumbo G, Teti A (2003) Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis. Am J Pathol 162:57–68PubMedCrossRefGoogle Scholar
  14. 14.
    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 18:1513–1518PubMedCrossRefGoogle Scholar
  15. 15.
    Gao G, Zhang ZL, Zhang H, Hu WW, Huang QR, Lu JH, Hu YQ, Li M, Liu YJ, He JW, Gu JM, Yu JB (2008) Hip axis length changes in 10,554 males and females and the association with femoral neck fracture. J Clin Densitom 11:360–366PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang ZL, He JW, Qin YJ, Hu YQ, Li M, Zhang H, Hu WW, Liu YJ, Gu JM (2008) Association between myostatin gene polymorphisms and peak BMD variation in Chinese nuclear families. Osteoporos Int 19:39–47PubMedCrossRefGoogle Scholar
  17. 17.
    Wu XP, Liao EY, Zhang H, Dai RC, Shan PF, Cao XZ, Liu SP, Jiang Y (2004) Determination of age-specific bone mineral density and comparison of diagnosis and prevalence of primary osteoporosis in Chinese women based on both Chinese and World Health Organization criteria. J Bone Miner Metab 22:382–391PubMedGoogle Scholar
  18. 18.
    Wu XP, Yang YH, Zhang H, Yuan LQ, Luo XH, Cao XZ, Liao EY (2005) Gender differences in bone density at different skeletal sites of acquisition with age in Chinese children and adolescents. J Bone Miner Metab 23:253–260PubMedCrossRefGoogle Scholar
  19. 19.
    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 74:42–46PubMedCrossRefGoogle Scholar
  20. 20.
    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 92:771–778PubMedCrossRefGoogle Scholar
  21. 21.
    Johnston CC Jr, Lavy N, Lord T, Vellios F, Merritt AD, Deiss WP Jr (1968) Osteopetrosis. A clinical, genetic, metabolic, and morphologic study of the dominantly inherited, benign form. Medicine (Baltimore) 47:149–167CrossRefGoogle Scholar
  22. 22.
    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 37:655–661PubMedCrossRefGoogle Scholar
  23. 23.
    Chu K, Snyder R, Econs MJ (2006) Disease status in autosomal dominant osteopetrosis type 2 is determined by osteoclastic properties. J Bone Miner Res 21:1089–1097PubMedCrossRefGoogle Scholar
  24. 24.
    Kajiya H, Okamoto F, Ohgi K, Nakao A, Fukushima H, Okabe K (2009) Characteristics of ClC7 Cl− channels and their inhibition in mutant (G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene-expressing cells. Pflugers Arch 458:1049–1059PubMedCrossRefGoogle Scholar
  25. 25.
    Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15:613–620PubMedCrossRefGoogle Scholar
  26. 26.
    Whyte MP, Chines A, Silva DP Jr, Landt Y, Ladenson JH (1996) Creatine kinase brain isoenzyme (BB-CK) presence in serum distinguishes osteopetroses among the sclerosing bone disorders. J Bone Miner Res 11:1438–1443PubMedCrossRefGoogle Scholar
  27. 27.
    Yoneyama T, Fowler HL, Pendleton JW, Sforza PP, Gerard RD, Lui CY, Eldridge TH, Iranmanesh A (1992) Elevated serum levels of creatine kinase BB in autosomal dominant osteopetrosis type II—a family study. Clin Genet 42:39–42PubMedCrossRefGoogle Scholar
  28. 28.
    Yoneyama T, Fowler HL, Pendleton JW, Sforza PP, Lui CY, Iranmanesh A, Gerard RD (1989) Elevated levels of creatine kinase BB isoenzyme in three patients with adult osteopetrosis. N Engl J Med 320:1284–1285PubMedGoogle Scholar
  29. 29.
    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 25:2515–2526PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2011

Authors and Affiliations

  • Chun Wang
    • 1
  • Hao Zhang
    • 1
  • Jin-Wei He
    • 1
  • Jie-Mei Gu
    • 1
  • Wei-Wei Hu
    • 1
  • Yun-Qiu Hu
    • 1
  • Miao Li
    • 1
  • Yu-Juan Liu
    • 1
  • Wen-Zhen Fu
    • 1
  • Hua Yue
    • 1
  • Yao-Hua Ke
    • 1
  • Zhen-Lin Zhang
    • 1
    Email author
  1. 1.Metabolic Bone Disease and Genetics Research Unit, Department of Osteoporosis and Bone DiseasesShanghai Sixth People’s Hospital Affiliated with Shanghai Jiao Tong UniversityShanghaiChina

Personalised recommendations