Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADO-II) and intermediate autosomal recessive osteopetrosis (IARO) in Chinese patients. Issue 3 (March 2016)

• Record Type: Journal Article
• Authors: Pang, Q.; Chi, Y.; Zhao, Z.; Xing, X.; Li, M.; Wang, O.; Jiang, Y.; Liao, R.; Sun, Y.; Dong, J.; Xia, W.
• Is Part Of: Osteoporosis international. Volume 27:Issue 3(2016)
• Page Start: 1047
• Page End: 1055
• Publication Date: 2016-03
• Subjects: Autosomal dominant osteopetrosis type II -- CLCN7 -- Clinical manifestation -- Intermediate autosomal recessive osteopetrosis -- Mutation -- Phenotype; Osteoporosis -- Periodicals; Bones -- Metabolism -- Disorders -- Periodicals; 616.716005
• DOI: 10.1007/s00198-015-3320-x
• Languages: English
• ISSNs: 0937-941X

Abstract

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 theCLCN7 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 theCLCN7 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 inCLCN7 are associated to ADO-II, while homozygous and compound heterozygous mutations inCLCN7 may result in ARO and IARO. To date, a total of 24 mutations inCLCN7 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 ofCLCN7 gene mutations in these patients. Methods All 25CLCN7 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 novelCLCN7 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 ofCLCN7 mutations and improve our understanding of this heritable bone disorder.