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Novel connexin 30 and connexin 26 mutational spectrum in patients with progressive sensorineural hearing loss

Published online by Cambridge University Press:  15 June 2012

S Battelino ,
B Repič Lampret ,
M Žargi  and
K Trebušak Podkrajšek
S Battelino
Affiliation:
Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana, Slovenia
B Repič Lampret
Affiliation:
Centre for Medical Genetics, University Children's Hospital, University Medical Centre Ljubljana, Slovenia
M Žargi
Affiliation:
Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana, Slovenia
K Trebušak Podkrajšek*
Affiliation:
Centre for Medical Genetics, University Children's Hospital, University Medical Centre Ljubljana, Slovenia
*
Address for correspondence: Dr Katarina Trebušak Podkrajšek, University Medical Centre Ljubljana, University Children's Hospital, Bohoričeva 20, SI-1252 Ljubljana, Slovenia Fax: +386 1 522 93 57 E-mail: katarina.trebusak@kclj.si
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Abstract

Objective:

Mutations in the gap junction protein beta-2 gene (‘GJB2’) are known to be responsible for mild to profound congenital and late-onset hearing loss. This study aimed to investigate the molecular basis of progressive hearing loss compared with non-progressive hearing loss.

Methods:

Following clinical otorhinolaryngological evaluation, a genetic analysis was performed in a cohort of 72 patients with progressive sensorineural hearing loss.

Results:

Pathological genotypes were established in 16 patients (22.2 per cent). Six different gap junction protein beta-2 gene mutations were detected in 15 patients, with the c.35delG mutation responsible for 56 per cent of the mutated alleles. A novel gap junction protein beta-6 gene (‘GJB6’) mutation (p.Met203Val) was observed in one patient with mild progressive hearing loss.

Conclusion:

Analyses of gap junction protein beta-2 and -6 genes revealed that similar pathological genotypes, occurring with similar frequencies, were responsible for progressive hearing loss, compared with reported genotypes for non-progressive hearing loss patients. Thus, genotype cannot be used to differentiate non-progressive from progressive hearing loss cases; in this study, patients both with and without an established pathological genotype had a similar clinical course.

Keywords

Hearing Loss, SensorineuralGeneticsConnexin 26Connexin 30

Information

Type
Main Articles
Information
The Journal of Laryngology & Otology , Volume 126 , Issue 8 , August 2012 , pp. 763 - 769
Copyright
Copyright © JLO (1984) Limited 2012

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References

1 Snoeckx, RL, Huygen, PL, Feldmann, D, Marlin, S, Denoyelle, F, Waligora, J et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet 2005;77:945–57CrossRefGoogle ScholarPubMed
2 Kenneson, A, Van Naarden, BK, Boyle, C. GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med 2002;4:258–74CrossRefGoogle ScholarPubMed
3 Welch, KO, Marin, RS, Pandya, A, Arnos, KS. Compound heterozygosity for dominant and recessive GJB2 mutations: effect on phenotype and review of the literature. Am J Med Genet A 2007;143A:1567–73CrossRefGoogle ScholarPubMed
4 Kenna, MA, Feldman, HA, Neault, MW, Frangulov, A, Wu, BL, Fligor, B et al. Audiologic phenotype and progression in GJB2 (connexin 26) hearing loss. Arch Otolaryngol Head Neck Surg 2010;136:81–7CrossRefGoogle ScholarPubMed
5 del Castillo, FJ, Rodriguez-Ballesteros, M, Alvarez, A, Hutchin, T, Leonardi, E, de Oliveira, CA et al. A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. J Med Genet 2005;42:588–94CrossRefGoogle Scholar
6 Del Castillo, I, Moreno-Pelayo, MA, del Castillo, FJ, Brownstein, Z, Marlin, S, Adina, Q et al. Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study. Am J Hum Genet 2003;73:1452–8CrossRefGoogle ScholarPubMed
7 Gallo-Teran, J, Morales-Angulo, C, Rodriguez-Ballesteros, M, Moreno-Pelayo, MA, Del Castillo, I, Moreno, F. Prevalence of the 35delG mutation in the GJB2 gene, del (GJB6-D13S1830) in the GJB6 gene, Q829X in the OTOF gene and A155 5G in the mitochondrial 12S rRNA gene in subjects with non-syndromic sensorineural hearing impairment of congenital/childhood onset [in Spanish]. Acta Otorrinolaringol Esp 2005;56:463–8Google Scholar
8 Fakhim, SA, Naderpoor, M, Shahidi, N, Basharhashemi, F, Nejati, N, Sakha, SH et al. Study of prevalence and causes of hearing loss in high risk neonates admitted to neonatal ward and neonatal intensive care unit. Int Adv Otol 2010;6:365–70Google Scholar
9 Bartsch, O, Vatter, A, Zechner, U, Kohlschmidt, N, Wetzig, C, Baumgart, A et al. GJB2 mutations and genotype-phenotype correlation in 335 patients from Germany with nonsyndromic sensorineural hearing loss: evidence for additional recessive mutations not detected by current methods. Audiol Neurootol 2010;15:375–82CrossRefGoogle Scholar
10 Kelsell, DP, Dunlop, J, Stevens, HP, Lench, NJ, Liang, JN, Parry, G et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 1997;387:80–3CrossRefGoogle ScholarPubMed
11 Matos, TD, Simoes-Teixeira, H, Caria, H, Rosa, H, O'Neill, A, Fialho, G. The controversial p.Arg12 7His mutation in GJB 2: report on three Portuguese hearing loss family cases. Genet Test Mol Biomarkers 2010;14:141–4CrossRefGoogle Scholar
12 Marlin, S, Garabedian, EN, Roger, G, Moatti, L, Matha, N, Lewin, P et al. Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. Arch Otolaryngol Head Neck Surg 2001;127:927–33CrossRefGoogle ScholarPubMed
13 Tsukada, K, Nishio, S, Usami, S. A large cohort study of GJB2 mutations in Japanese hearing loss patients. Clin Genet 2010;78:464–70CrossRefGoogle ScholarPubMed
14 Den Dunnen, JT, Antonarakis, SE. Nomenclature for the description of human sequence variations. Hum Genet 2001;109:121–4CrossRefGoogle ScholarPubMed
15 Cama, E, Melchionda, S, Palladino, T, Carella, M, Santarelli, R, Genovese, E et al. Hearing loss features in GJB2 biallelic mutations and GJB2/GJB6 digenic inheritance in a large Italian cohort. Int J Audiol 2009;48:12–17 CrossRefGoogle Scholar
16 Primignani, P, Trotta, L, Castorina, P, Lalatta, F, Sironi, F, Radaelli, C et al. Analysis of the GJB2 and GJB6 genes in Italian patients with nonsyndromic hearing loss: frequencies, novel mutations, genotypes, and degree of hearing loss. Genet Test Mol Biomarkers 2009;13:209–17CrossRefGoogle ScholarPubMed
17 Putcha, GV, Bejjani, BA, Bleoo, S, Booker, JK, Carey, JC, Carson, N et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med 2007;9:413–26CrossRefGoogle Scholar
18 Marlin, S, Feldmann, D, Blons, H, Loundon, N, Rouillon, I, Albert, S et al. GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. Arch Otolaryngol Head Neck Surg 2005;131:481–7CrossRefGoogle Scholar
19 Sansovic, I, Knezevic, J, Musani, V, Seeman, P, Barisic, I, Pavelic, J. GJB 2 mutations in patients with nonsyndromic hearing loss from Croatia. Genet Test Mol Biomarkers 2009;13:693–9CrossRefGoogle Scholar
20 Frei, K, Ramsebner, R, Lucas, T, Baumgartner, WD, Schoefer, C, Wachtler, FJ et al. Screening for monogenetic del(GJB6-D13S1830) and digenic del(GJB6-D13S1830)/GJB2 patterns of inheritance in deaf individuals from Eastern Austria. Hear Res 2004;196:115–18CrossRefGoogle ScholarPubMed
21 Chang, Q, Tang, W, Ahmad, S, Stong, B, Leu, G, Lin, X. Functional studies reveal new mechanisms for deafness caused by connexin mutations. Otol Neurotol 2009;30:237–40CrossRefGoogle ScholarPubMed
22 Chang, Q, Tang, W, Ahmad, S, Zhou, B, Lin, X. Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice. PLoS ONE 2008;3:e4088CrossRefGoogle ScholarPubMed
23 Kyte, J, Doolittle, RF. A simple method for displaying the hydropathic character of a protein. J Mol Biol 1982;157:105–32CrossRefGoogle ScholarPubMed
24 Sun, Y, Tang, W, Chang, Q, Wang, Y, Kong, W, Lin, X. Connexin 30 null and conditional connexin 26 null mice display distinct pattern and time course of cellular degeneration in the cochlea. J Comp Neurol 2009;516:569–79CrossRefGoogle ScholarPubMed
25 Grifa, A, Wagner, CA, D'Ambrosio, L, Melchionda, S, Bernardi, F, Lopez-Bigas, N et al. Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet 1999;23:16–18 CrossRefGoogle ScholarPubMed
26 Denoyelle, F, Lina-Granade, G, Plauchu, H, Bruzzone, R, Chaib, H, Levi-Acobas, F et al. Connexin 26 gene linked to a dominant deafness. Nature 1998;393:319–20CrossRefGoogle ScholarPubMed
27 Tekin, M, Arnos, KS, Xia, XJ, Oelrich, MK, Liu, XZ, Nance, WE et al. W44C mutation in the connexin 26 gene associated with dominant non-syndromic deafness. Clin Genet 2001;59:269–73CrossRefGoogle ScholarPubMed
28 Loffler, J, Nekahm, D, Hirst-Stadlmann, A, Gunther, B, Menzel, HJ, Utermann, G et al. Sensorineural hearing loss and the incidence of Cx26 mutations in Austria. Eur J Hum Genet 2001;9:226–30CrossRefGoogle ScholarPubMed
29 Morle, L, Bozon, M, Alloisio, N, Latour, P, Vandenberghe, A, Plauchu, H et al. A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss. J Med Genet 2000;37:368–70CrossRefGoogle ScholarPubMed