Analysis of Genetic Variations in Connexin 26 (GJB2) Gene among Nonsyndromic Hearing Impairment: Familial Study

Abstract

Objective The goal of this research was to investigate the gap junction beta 2 (GJB2) gene mutations associated with nonsyndromic hearing loss individuals in North Karnataka, India.

Materials and Methods For this study, patients with sensorineural genetic hearing abnormalities and a family history of deafness were included. A total of 35 patients from 20 families have been included in the study. The patient's DNA was isolated from peripheral blood samples. The GJB2 gene coding region was analyzed through Sanger sequencing.

Results There is no changes in the first exon of the GJB2 gene. Nine different variants were recorded in second exon of the targeted gene. W24X and W77X are two nonsense mutations and three polymorphisms viz. R127H, V153I, and I33T were reported along with four 3′-UTR variants. A total (9/20) of 45% of families have been identified with mutations in the targeted gene.

Conclusion GJB2 mutations were identified in 19 deaf-mute patients (19/35), and 13 patients were homozygous for the mutations identified in our study cohort. In our study, W24X mutation was found to be the pathogenic with a high percentage, prompting further evaluation of the other genes, along with the study of additional genetic or external causes in the families, which is essential.

Keywords

variation - familial - nonsyndromic hearing Impairment - GJB2 - connexin 26

• References

• 1 Godbole K, Hemavathi J, Vaid N, Pandit AN, Sandeep MN, Chandak GR. Low prevalence of GJB2 mutations in non-syndromic hearing loss in Western India. Indian J Otolaryngol Head Neck Surg 2010; 62 (01) 60-63
• 2 Kamiya K. Inner ear cell therapy targeting hereditary deafness by activation of stem cell homing factors. Front Pharmacol 2015; 6: 2
• 3 Sarmadi A, Nasrniya S, Narrei S, Nouri Z, Abtahi H, Tabatabaiefar MA. Whole exome sequencing identifies novel compound heterozygous pathogenic variants in the MYO15A gene leading to autosomal recessive non-syndromic hearing loss. Mol Biol Rep 2020; 47 (07) 5355-5364
• 4 Yu X, Lin Y, Xu J. et al. Molecular epidemiology of Chinese Han deaf patients with bi-allelic and mono-allelic GJB2 mutations. Orphanet J Rare Dis 2020; 15 (01) 29
• 5 RamShankar M, Girirajan S, Dagan O. et al. Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India. J Med Genet 2003; 40 (05) e68
• 6 Del Castillo FJ, Del Castillo I. DFNB1 non-syndromic hearing impairment: diversity of mutations and associated phenotypes. Front Mol Neurosci 2017; 10: 428
• 7 Bennett BC, Purdy MD, Baker KA. et al. An electrostatic mechanism for Ca(2+)-mediated regulation of gap junction channels. Nat Commun 2016; 7: 8770
• 8 Banjara H, Mungutwar V, Swarnkar N, Patra P. Detection of connexin 26 gene (GJB2) mutations in cases of congenital non syndromic deafness. Indian J Otolaryngol Head Neck Surg 2016; 68 (02) 248-253
• 9 Koohiyan M. Identification and clinical implications of a novel pathogenic variant in the GJB2 gene causes autosomal recessive non-syndromic hearing loss in a consanguineous Iranian family. Intractable Rare Dis Res 2020; 9 (01) 30-34
• 10 Fukunaga I, Shirai K, Oe Y. et al. Generation of two induced pluripotent stem cell lines from PBMCs of siblings carrying c.235delC mutation in the GJB2 gene associated with sensorineural hearing loss. Stem Cell Res (Amst) 2020; 47: 101910
• 11 Chan DK, Chang KW. GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope 2014; 124 (02) E34-E53
• 12 Kelsell DP, Dunlop J, Stevens HP. et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 1997; 387 (6628): 80-83
• 13 Vanniya S P, Chandru J, Pavithra A. et al. Recurrence of reported CDH23 mutations causing DFNB12 in a special cohort of South Indian hearing impaired assortative mating families - an evaluation. Ann Hum Genet 2018; 82 (02) 119-126
• 14 Subathra M, Selvakumari M, Ramesh A. et al. Complete mitochondrial genome analysis and clinical documentation of a five-generational Indian family with mitochondrial 1555A>G mutation and postlingual hearing loss. Ann Hum Genet 2014; 78 (03) 217-234
• 15 Sobe T, Erlich P, Berry A. et al. High frequency of the deafness-associated 167delT mutation in the connexin 26 (GJB2) gene in Israeli Ashkenazim. Am J Med Genet 1999; 86 (05) 499-500
• 16 Abe S, Usami S, Shinkawa H, Kelley PM, Kimberling WJ. Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet 2000; 37 (01) 41-43
• 17 Van Laer L, Coucke P, Mueller RF. et al. A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment. J Med Genet 2001; 38 (08) 515-518
• 18 Liu XZ, Xia XJ, Ke XM. et al. The prevalence of connexin 26 ( GJB2) mutations in the Chinese population. Hum Genet 2002; 111 (4-5): 394-397
• 19 Maheshwari M, Vijaya R, Ghosh M, Shastri S, Kabra M, Menon PS. Screening of families with autosomal recessive non-syndromic hearing impairment (ARNSHI) for mutations in GJB2 gene: Indian scenario. Am J Med Genet A 2003; 120A [phone]
• 20 Ming-kun H, Dong-yi H, Yu-fen G. et al. Screening of GJB2 mutations in Chinese population. J Otol 2007; 2 (01) 18-22
• 21 Joseph AY, Rasool TJ. High frequency of connexin 26 (GJB2) mutations associated with nonsyndromic hearing loss in the population of Kerala, India. Int J Pediatr Otorhinolaryngol 2009; 73 (03) 437-443
• 22 Adhikary B, Ghosh S, Paul S. et al. Spectrum and frequency of GJB2, GJB6 and SLC26A4 gene mutations among nonsyndromic hearing loss patients in eastern part of India. Gene 2015; 573 (02) 239-245
• 23 Ramchander P, Nandur V, Dwarakanath K, Vishnupriya S, Padma T. Prevalence of Cx26 (GJB2) gene mutations causing recessive nonsyndromic hearing impairment in India. Int J Hum Genet 2005; 5 (04) 241-246
• 24 Mani RS, Ganapathy A, Jalvi R. et al. Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss. Eur J Hum Genet 2009; 17 (04) 502-509
• 25 Padma G, Ramchander PV, Nandur UV, Padma T. GJB2 and GJB6 gene mutations found in Indian probands with congenital hearing impairment. J Genet 2009; 88 (03) 267-272
• 26 Scott DA, Kraft ML, Stone EM, Sheffield VC, Smith RJ. Connexin mutations and hearing loss. Nature 1998; 391 (6662): 32
• 27 Bhalla S, Sharma R, Khandelwal G, Panda NK, Khullar M. Low incidence of GJB2, GJB6 and mitochondrial DNA mutations in North Indian patients with non-syndromic hearing impairment. Biochem Biophys Res Commun 2009; 385 (03) 445-448