Novel CLCN7 mutations cause autosomal dominant osteopetrosis type II and intermediate autosomal recessive osteopetrosis

  • Authors:
    • Li Li
    • Shan-Shan Lv
    • Chun Wang
    • Hua Yue
    • Zhen-Lin Zhang
  • View Affiliations

  • Published online on: April 3, 2019     https://doi.org/10.3892/mmr.2019.10123
  • Pages: 5030-5038
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Osteopetrosis refers to a group of rare genetic bone diseases that are clinically characterized by increased bone mass and fragility. The principal pathogenic defect in patients with chloride channel 7 (CLCN7) gene‑dependent osteopetrosis is reduced osteoclast activity, which leads to decreased bone resorption. Mutations in the CLCN7 gene result in autosomal dominant osteopetrosis type II (ADO‑II), autosomal recessive osteopetrosis (ARO) and intermediate ARO (IARO). In the present study, eight mutations in the CLCN7 gene were identified in six patients with familial osteopetrosis and one patient with sporadic osteopetrosis. Heterozygous mutations c.856C>T (R286W), c.2236T>G (Y746D), c.296A>G (Y99C) and c.937G>A (E313K), and a splice mutation (c.2232‑2A>G) in the CLCN7 gene were detected in patients with ADO‑II. A homozygous mutation c.2377G>C (G793R), and a compound heterozygous mutation c.1409C>T (P470L) and c.647_648dupTG (K217X) were detected in two Chinese families with IARO. Among these mutations, two heterozygous mutations (c.2236T>G and c.2232‑2A>G), one homozygous mutation (c.2377G>C) and the compound heterozygous mutation (c.1409C>T and c.647_648dupTG) are novel, to the best of our knowledge. The present findings not only broaden the allelic spectrum of CLCN7 mutations, but also provide increased knowledge of the clinical phenotypes observed in Chinese patients with osteopetrosis.

References

1 

Del Fattore A, Cappariello A and Teti A: Genetics, pathogenesis and complications of osteopetrosis. Bone. 42:19–29. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Coudert AE, de Vernejoul MC, Muraca M and Del Fattore A: Osteopetrosis and its relevance for the discovery of new functions associated with the skeleton. Int J Endocrinol. 2015:3721562015. View Article : Google Scholar : PubMed/NCBI

3 

Palagano E, Blair HC, Pangrazio A, Tourkova I, Strina D, Angius A, Cuccuru G, Oppo M, Uva P, Van Hul W, et al: Buried in the middle but guilty: Intronic mutations in the TCIRG1 gene cause human autosomal recessive osteopetrosis. J Bone Miner Res. 30:1814–1821. 2015. View Article : Google Scholar : PubMed/NCBI

4 

Tolar J, Teitelbaum S and Orchard P: Osteopetrosis. N Engl J Med. 351:2839–2849. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Cleiren E, Bénichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, Beaverson K, Aledo A, Whyte MP, Yoneyama T, et al: Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet. 10:2861–2867. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Bénichou O, Cleiren E, Gram J, Bollerslev J, de Vernejoul MC and Van Hul W: Mapping of autosomal dominant osteopetrosis type II (Albers-Schönberg disease) to chromosome 16p13.3. Am J Hum Genet. 69:647–654. 2001. View Article : Google Scholar : PubMed/NCBI

7 

Cappariello A, Maurizi A, Veeriah V and Teti A: Reprint of: The great beauty of the osteoclast. Arch Biochem Biophys. 561:13–21. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Teti A: Bone development: Overview of bone cells and signaling. Curr Osteoporos Rep. 9:264–273. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Kuroyanagi Y, Kawasaki H, Noda Y, Ohmachi T, Sekiya S, Yoshimura K, Ohe C, Michigami T, Ozono K and Kaneko K: A fatal case of infantile malignant osteopetrosis complicated by pulmonary arterial hypertension after hematopoietic stem cell transplantation. Tohoku J Exp Med. 234:309–312. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Zheng H, Shao C, Zheng Y, He JW, Fu WZ, Wang C and Zhang ZL: Two novel mutations of CLCN7 gene in Chinese families with autosomal dominant osteopetrosis (type II). J Bone Miner Metab. 34:440–446. 2016. View Article : Google Scholar : PubMed/NCBI

11 

Deng H, He D, Rong P, Xu H, Yuan L, Li L, Lu Q and Guo Y: Novel CLCN7 mutation identified in a Han Chinese family with autosomal dominant osteopetrosis-2. Mol Pain. 12:17448069166526282016. View Article : Google Scholar : PubMed/NCBI

12 

Faden MA, Krakow D, Ezgu F, Rimoin DL and Lachman RS: The Erlenmeyer flask bone deformity in the skeletal dysplasias. Am J Med Genet A 149A. 1334–1345. 2009. View Article : Google Scholar

13 

Boudin E and Van Hul W: Sclerosing bone dysplasias. Best Pract Res Clin Endocrinol Metab. 32:707–723. 2018. View Article : Google Scholar : PubMed/NCBI

14 

Zhang ZL, He JW, Zhang H, Hu WW, Fu WZ, Gu JM, Yu JB, Gao G, Hu YQ, Li M and Liu YJ: Identification of the CLCN7 gene mutations in two Chinese families with autosomal dominant osteopetrosis (type II). J Bone Miner Metab. 27:444–451. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Wang C, Zhang H, He JW, Gu JM, Hu WW, Hu YQ, Li M, Liu YJ, Fu WZ, Yue H, et al: 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. 30:338–348. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Zhang X, Wei Z, He J, Wang C and Zhang Z: Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADOII) and intermediate autosomal recessive osteopetrosis (ARO) in seven Chinese families. Postgrad Med. 129:934–942. 2017. View Article : Google Scholar : PubMed/NCBI

17 

Xue Y, Wang W, Mao T and Duan X: Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia. J Craniomaxillofac Surg. 40:416–420. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Zeng B, Li R, Hu Y, Hu B, Zhao Q, Liu H, Yuan P and Wang Y: A novel mutation and a known mutation in the CLCN7 gene associated with relatively stable infantile malignant osteopetrosis in a Chinese patient. Gene. 576:176–181. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Pang Q, Chi Y, Zhao Z, Xing X, Li M, Wang O, Jiang Y, Liao R, Sun Y, Dong J and Xia W: Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADO-II) and intermediate autosomal recessive osteopetrosis (IARO) in Chinese patients. Osteoporos Int. 27:1047–1055. 2016. View Article : Google Scholar : PubMed/NCBI

20 

Zheng H, Zhang Z, He JW, Fu WZ, Wang C and Zhang ZL: Identification of two novel CLCN7 gene mutations in three Chinese families with autosomal dominant osteopetrosis type II. Joint Bone Spine. 81:188–189. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS and Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods. 7:248–249. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Lange PF, Wartosch L, Jentsch TJ and Fuhrmann JC: ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature. 440:220–223. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Sobacchi C, Schulz A, Coxon FP, Villa A and Helfrich MH: Osteopetrosis: Genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 9:522–536. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Villa A, Guerrini MM, Cassani B, Pangrazio A and Sobacchi C: Infantile malignant, autosomal recessive osteopetrosis: The rich and the poor. Calcif Tissue Int. 84:1–12. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Waguespack SG, Hui SL, Dimeglio LA and Econs MJ: Autosomal dominant osteopetrosis: Clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation. J Clin Endocrinol Metab. 92:771–778. 2007. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 19 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Li, L., Lv, S., Wang, C., Yue, H., & Zhang, Z. (2019). Novel CLCN7 mutations cause autosomal dominant osteopetrosis type II and intermediate autosomal recessive osteopetrosis. Molecular Medicine Reports, 19, 5030-5038. https://doi.org/10.3892/mmr.2019.10123
MLA
Li, L., Lv, S., Wang, C., Yue, H., Zhang, Z."Novel CLCN7 mutations cause autosomal dominant osteopetrosis type II and intermediate autosomal recessive osteopetrosis". Molecular Medicine Reports 19.6 (2019): 5030-5038.
Chicago
Li, L., Lv, S., Wang, C., Yue, H., Zhang, Z."Novel CLCN7 mutations cause autosomal dominant osteopetrosis type II and intermediate autosomal recessive osteopetrosis". Molecular Medicine Reports 19, no. 6 (2019): 5030-5038. https://doi.org/10.3892/mmr.2019.10123