A novel compound heterozygous mutation in the GJB2 gene causing non-syndromic hearing loss in a family

Wei,Qinjun; Liu,Youguo; Wang,Shuai; Liu,Tingting; Lu,Yajie; Xing,Guangqian; Cao,Xin

doi:10.3892/ijmm.2013.1581

2014-February Volume 33 Issue 2

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2014-February Volume 33 Issue 2

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A novel compound heterozygous mutation in the GJB2 gene causing non-syndromic hearing loss in a family

Authors:
- Qinjun Wei
- Youguo Liu
- Shuai Wang
- Tingting Liu
- Yajie Lu
- Guangqian Xing
- Xin Cao
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Affiliations: Department of Biotechnology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Department of Otolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China

Copyright: © Wei et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
Pages: 310-316
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Published online on: December 9, 2013

https://doi.org/10.3892/ijmm.2013.1581
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Abstract

Mutations in the GJB2 gene are responsible for up to 50% of cases of non-syndromic recessive hearing loss, with c.35delG, c.167delT and c.235delC being the predominant mutations in many world populations. However, a large number of rare mutations in this gene may also contribute to hearing loss. The aim of the present study was to conduct a clinical and molecular characterization of a Chinese family with non-syndromic hearing loss. Sequence analysis of the GJB2 gene led to the identification of a novel compound heterozygous mutation c.257C>G (p.T86R)/c.605ins46 in two profoundly deaf siblings whose hearing parents were each heterozygous, either for the c.257C>G (paternal) or for the c.605ins46 (maternal) mutations. Both c.257C>G and c.605ins46 are rare GJB2 mutations that have previously been reported to segregate with autosomal recessive hearing loss exclusively in East Asian populations. To study the pathogenic effect of the compound heterozygous mutation, a three-dimensional model was constructed and Anolea mean force potential energy was predicted for a bioinformatic structural analysis. HEK293 cells were used to study the pathogenic effect of mutant connexin 26 proteins. The results suggested that the c.257C>G (p.T86R)/c.605ins46 mutations in the GJB2 gene provides a novel molecular explanation for the role of the GJB2 gene in hearing loss.

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1	Morton CC: Genetics, genomics and gene discovery in the auditory system. Hum Mol Genet. 11:1229–1240. 2002. View Article : Google Scholar : PubMed/NCBI
2	Hilgert N, Smith RJ and Campa G: Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics. Mutat Res. 681:189–196. 2009. View Article : Google Scholar : PubMed/NCBI
3	Kenneson A, Van Naarden Braun K and Boyle C: GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med. 4:258–274. 2002. View Article : Google Scholar : PubMed/NCBI
4	Estivill X, Fortina P, Surrey S, et al: Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 351:394–398. 1998. View Article : Google Scholar : PubMed/NCBI
5	Morell RJ, Kim HJ, Hood LJ, et al: Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med. 339:1500–1505. 1998. View Article : Google Scholar : PubMed/NCBI
6	Abe S, Usami S, Shinkawa H, Kelley PM and Kimberling WJ: Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet. 37:41–43. 2000. View Article : Google Scholar : PubMed/NCBI
7	Sobe T, Vreugde S, Shahin H, et al: The prevalence and expression of inherited connexin 26 mutations associated with nonsyndromic hearing loss in the Israeli population. Hum Genet. 106:50–57. 2000. View Article : Google Scholar : PubMed/NCBI
8	Dai P, Yu F, Han B, et al: GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. J Transl Med. 7:262009. View Article : Google Scholar : PubMed/NCBI
9	Li CX, Pan Q, Guo YG, et al: Construction of a multiplex allele-specific PCR-based universal array (ASPUA) and its application to hearing loss screening. Hum Mutat. 29:306–314. 2008. View Article : Google Scholar : PubMed/NCBI
10	Arnold K, Bordoli L, Kopp J and Schwede T: The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics. 22:195–201. 2006. View Article : Google Scholar : PubMed/NCBI
11	Schwede T, Kopp J, Guex N and Peitsch MC: SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res. 31:3381–3385. 2003. View Article : Google Scholar : PubMed/NCBI
12	Guex N and Peitsch MC: SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis. 18:2714–2723. 1997. View Article : Google Scholar : PubMed/NCBI
13	Maeda S, Nakagawa S, Suga M, Yamashita E, Oshima A, Fujiyoshi Y and Tsukihara T: Structure of the connexin 26 gap junction channel at 3.5 A resolution. Nature. 458:597–602. 2009. View Article : Google Scholar : PubMed/NCBI
14	Lee KY, Choi SY, Bae JW, et al: Molecular analysis of the GJB2, GJB6 and SLC26A4 genes in Korean deafness patients. Int J Pediatr Otorhinolaryngol. 72:1301–1309. 2008. View Article : Google Scholar : PubMed/NCBI
15	Choi SY, Park HJ, Lee KY, et al: Different functional consequences of two missense mutations in the GJB2 gene associated with non-syndromic hearing loss. Hum Mutat. 30:E716–E727. 2009. View Article : Google Scholar : PubMed/NCBI
16	Yuge I, Ohtsuka A, Matsunaga T and Usami S: Identification of 605ins46, a novel GJB2 mutation in a Japanese family. Auris Nasus Larynx. 29:379–382. 2002. View Article : Google Scholar : PubMed/NCBI
17	Murgia A, Orzan E, Polli R, et al: Cx26 deafness: mutation analysis and clinical variability. J Med Genet. 36:829–832. 1999.PubMed/NCBI
18	Cohn ES, Kelley PM, Fowler TW, et al: Clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene (GJB2/DFNB1). Pediatrics. 103:546–550. 1999. View Article : Google Scholar : PubMed/NCBI
19	Wang WH, Liu YF, Su CC, Su MC, Li SY and Yang JJ: A novel missense mutation in the connexin30 causes nonsyndromic hearing loss. PLoS One. 6:e214732011. View Article : Google Scholar : PubMed/NCBI
20	Anfinsen CB: Principles that govern the folding of protein chains. Science. 181:223–230. 1973. View Article : Google Scholar : PubMed/NCBI
21	Han SH, Park HJ, Kang EJ, Ryu JS, Lee A, Yang YH and Lee KR: Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. J Hum Genet. 53:1022–1028. 2008. View Article : Google Scholar : PubMed/NCBI
22	Mani RS, Ganapathy A, Jalvi R, et al: Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss. Eur J Hum Genet. 17:502–509. 2009. View Article : Google Scholar : PubMed/NCBI
23	Pollak A, Skórka A, Mueller-Malesińska M, et al: M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Am J Med Genet. 143A:2534–2543. 2007. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

A novel compound heterozygous mutation in the GJB2 gene causing non-syndromic hearing loss in a family

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