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Zahedi Abghari, Fateme, Mohseni, Marzieh, Esmaeilzadeh, Emran, Ghasemi, Hossein, Khorram Khorshid, Hamid Reza, Najafipour, Reza. (1405). Clinical and Genetic Characterization of Gap Junction Protein β-6 Variants in Non-Syndromic Hearing Loss: A Case Report with Familial Evaluation and In Silico Analyses. سامانه مدیریت نشریات علمی, 51(8), 592-602. doi: 10.30476/ijms.2026.109418.4473
Fateme Zahedi Abghari; Marzieh Mohseni; Emran Esmaeilzadeh; Hossein Ghasemi; Hamid Reza Khorram Khorshid; Reza Najafipour. "Clinical and Genetic Characterization of Gap Junction Protein β-6 Variants in Non-Syndromic Hearing Loss: A Case Report with Familial Evaluation and In Silico Analyses". سامانه مدیریت نشریات علمی, 51, 8, 1405, 592-602. doi: 10.30476/ijms.2026.109418.4473
Zahedi Abghari, Fateme, Mohseni, Marzieh, Esmaeilzadeh, Emran, Ghasemi, Hossein, Khorram Khorshid, Hamid Reza, Najafipour, Reza. (1405). 'Clinical and Genetic Characterization of Gap Junction Protein β-6 Variants in Non-Syndromic Hearing Loss: A Case Report with Familial Evaluation and In Silico Analyses', سامانه مدیریت نشریات علمی, 51(8), pp. 592-602. doi: 10.30476/ijms.2026.109418.4473
Zahedi Abghari, Fateme, Mohseni, Marzieh, Esmaeilzadeh, Emran, Ghasemi, Hossein, Khorram Khorshid, Hamid Reza, Najafipour, Reza. Clinical and Genetic Characterization of Gap Junction Protein β-6 Variants in Non-Syndromic Hearing Loss: A Case Report with Familial Evaluation and In Silico Analyses. سامانه مدیریت نشریات علمی, 1405; 51(8): 592-602. doi: 10.30476/ijms.2026.109418.4473

Clinical and Genetic Characterization of Gap Junction Protein β-6 Variants in Non-Syndromic Hearing Loss: A Case Report with Familial Evaluation and In Silico Analyses

Iranian Journal of Medical Sciences
مقاله 7، دوره 51، شماره 8، آبان 2026، صفحه 592-602    اصل مقاله (1.25 M)
نوع مقاله: Case Report(s)
شناسه دیجیتال (DOI): 10.30476/ijms.2026.109418.4473
نویسندگان
Fateme Zahedi Abghari؛ Marzieh Mohseni؛ Emran Esmaeilzadeh؛ Hossein Ghasemi؛ Hamid Reza Khorram Khorshid؛ Reza Najafipour*
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
چکیده
Non-syndromic sensorineural hearing loss (NSHL) exhibits substantial genetic heterogeneity, and the identification of its causative variants remains an important challenge. The gap junction protein β-6 (GJB6), expressed in multiple tissues including the sensory epithelium of the inner ear, is essential for auditory function. Although large GJB6 deletions are well characterized, single-nucleotide variants (SNVs) have been reported infrequently, and their pathogenic significance remains insufficiently defined. In this study, we identified a novel homozygous missense variant in GJB6, NM_001110219.3:c.446C>T (p.Ala149Val), through whole-exome sequencing and confirmed it by Sanger sequencing in a 32-year-old Iranian female from a consanguineous family, presenting with prelingual bilateral sensorineural hearing loss without any additional phenotypes or syndromic features. She was referred to the Medical Genetics Laboratory in Tehran, Iran, in March 2025. In silico predictions, mammalian conservation, and structural modeling suggest that this substitution may disrupt normal GJB6 function. To contextualize this finding, we reviewed all reported SNVs in GJB6, identifying 20 distinct variants in 47 patients, with most mutations clustering in the extracellular loop 1, cytoplasmic loop, transmembrane domain 3, and extracellular loop 2. These results expand the mutational spectrum of GJB6 and highlight its critical role in NSHL pathogenesis. Collectively, this study presents the first comprehensive report of SNVs in GJB6 and supports their further investigation in the genetic architecture of hereditary hearing loss.

تازه های تحقیق

Fateme Zahedi Abghari (Google Scholar)

Reza Najafipour (Google Scholar)

کلیدواژه‌ها
Hearing loss؛ Sensorineural؛ Whole exome sequencing؛ Point mutation
مراجع
  1. Alkhidir S, El-Akouri K, Al-Dewik N, Khodjet-El-Khil H, Okashah S, Islam N, et al. The genetic basis and the diagnostic yield of genetic testing related to nonsyndromic hearing loss in Qatar. Sci Rep. 2024;14:4202. doi: 10.1038/s41598-024-52784-z. PubMed PMID: 38378725; PubMed Central PMCID: PMC10879212.
  2. Morgan A, Lenarduzzi S, Cappellani S, Pecile V, Morgutti M, Orzan E, et al. Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations. Front Genet. 2018;9:681. doi: 10.3389/fgene.2018.00681. PubMed PMID: 30622556; PubMed Central PMCID: PMC6309105.
  3. Limmon R, Punagi AQ, Gaffar M, Idris I, Halik H. The variants and prevalence of the GJB2 and GJB6 in patients with non-syndromic congenital sensorineural hearing loss in Maluku, Indonesia. The Egyptian Journal of Otolaryngology. 2025;41:167. doi: 10.1186/s43163-025-00918-z.
  4. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215. doi: 10.1093/nar/16.3.1215. PubMed PMID: 3344216; PubMed Central PMCID: PMC334765.
  5. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. doi: 10.1038/gim.2015.30. PubMed PMID: 25741868; PubMed Central PMCID: PMC4544753.
  6. 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;23:16-8. doi: 10.1038/12612. PubMed PMID: 10471490.
  7. Yang JJ, Huang SH, Chou KH, Liao PJ, Su CC, Li SY. Identification of mutations in members of the connexin gene family as a cause of nonsyndromic deafness in Taiwan. Audiol Neurootol. 2007;12:198-208. doi: 10.1159/000099024. PubMed PMID: 17259707.
  8. Nemoto-Hasebe I, Akiyama M, Kudo S, Ishiko A, Tanaka A, Arita K, et al. Novel mutation p.Gly59Arg in GJB6 encoding connexin 30 underlies palmoplantar keratoderma with pseudoainhum, knuckle pads and hearing loss. Br J Dermatol. 2009;161:452-5. doi: 10.1111/j.1365-2133.2009.09137.x. PubMed PMID: 19416251.
  9. Asma A, Ashwaq A, Norzana AG, Atmadini AM, Ruszymah BH, Saim L, et al. The association between GJB2 mutation and GJB6 gene in non syndromic hearing loss school children. Med J Malaysia. 2011;66:124-8. PubMed PMID: 22106692.
  10. Battelino S, Repic Lampret B, Zargi M, Podkrajsek KT. Novel connexin 30 and connexin 26 mutational spectrum in patients with progressive sensorineural hearing loss. J Laryngol Otol. 2012;126:763-9. doi: 10.1017/S0022215112001119. PubMed PMID: 22704424.
  11. Oh SK, Choi SY, Yu SH, Lee KY, Hong JH, Hur SW, et al. Evaluation of the pathogenicity of GJB3 and GJB6 variants associated with nonsyndromic hearing loss. Biochim Biophys Acta. 2013;1832:285-91. doi: 10.1016/j.bbadis.2012.05.009. PubMed PMID: 22617145.
  12. Miyagawa M, Naito T, Nishio SY, Kamatani N, Usami S. Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients. PLoS One. 2013;8:e71381. doi: 10.1371/journal.pone.0071381. PubMed PMID: 23967202; PubMed Central PMCID: PMC3742761.
  13. Beck C, Perez-Alvarez JC, Sigruener A, Haubner F, Seidler T, Aslanidis C, et al. Identification and genotype/phenotype correlation of mutations in a large German cohort with hearing loss. Eur Arch Otorhinolaryngol. 2015;272:2765-76. doi: 10.1007/s00405-014-3157-5. PubMed PMID: 25214170.
  14. Pandey N, Xavier DF, Chatterjee A, Mani RS, Hiremagalore R, Tharakan A, et al. Functional Analysis of a Novel Connexin30 Mutation in a Large Family with Hearing Loss, Pesplanus, Ichthyosis, Cutaneous Nodules, and Keratoderma. Ann Hum Genet. 2016;80:11-9. doi: 10.1111/ahg.12141. PubMed PMID: 26620415.
  15. Alkowari MK, Vozzi D, Bhagat S, Krishnamoorthy N, Morgan A, Hayder Y, et al. Targeted sequencing identifies novel variants involved in autosomal recessive hereditary hearing loss in Qatari families. Mutat Res. 2017;800-802:29-36. doi: 10.1016/j.mrfmmm.2017.05.001. PubMed PMID: 28501645.
  16. Nonose RW, Lezirovitz K, de Mello Auricchio MTB, Batissoco AC, Yamamoto GL, Mingroni-Netto RC. Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects. BMC Med Genet. 2018;19:73. doi: 10.1186/s12881-018-0585-x. PubMed PMID: 29739340; PubMed Central PMCID: PMC5941635.
  17. Amritkumar P, Jeffrey JM, Chandru J, Vanniya SP, Kalaimathi M, Ramakrishnan R, et al. Role of DFNB1 mutations in hereditary hearing loss among assortative mating hearing impaired families from South India. BMC Med Genet. 2018;19:105. doi: 10.1186/s12881-018-0609-6. PubMed PMID: 29921236; PubMed Central PMCID: PMC6008914.
  18. Schutz M, Scimemi P, Majumder P, De Siati RD, Crispino G, Rodriguez L, et al. The human deafness-associated connexin 30 T5M mutation causes mild hearing loss and reduces biochemical coupling among cochlear non-sensory cells in knock-in mice. Hum Mol Genet. 2010;19:4759-73. doi: 10.1093/hmg/ddq402. PubMed PMID: 20858605; PubMed Central PMCID: PMC2989887.
  19. Wang WH, Liu YF, Su CC, Su MC, Li SY, Yang JJ. A novel missense mutation in the connexin30 causes nonsyndromic hearing loss. PLoS One. 2011;6:e21473. doi: 10.1371/journal.pone.0021473. PubMed PMID: 21731760; PubMed Central PMCID: PMC3123352.
  20. Zhang Y, Hao H. Conserved glycine at position 45 of major cochlear connexins constitutes a vital component of the Ca(2)(+) sensor for gating of gap junction hemichannels. Biochem Biophys Res Commun. 2013;436:424-9. doi: 10.1016/j.bbrc.2013.05.118. PubMed PMID: 23756814.
  21. Berger AC, Kelly JJ, Lajoie P, Shao Q, Laird DW. Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies. J Cell Sci. 2014;127:1751-64. doi: 10.1242/jcs.138230. PubMed PMID: 24522190.
  22. Mammano F. Inner Ear Connexin Channels: Roles in Development and Maintenance of Cochlear Function. Cold Spring Harb Perspect Med. 2019;9. doi: 10.1101/cshperspect.a033233. PubMed PMID: 30181354; PubMed Central PMCID: PMC6601451.
  23. Sommen M, Schrauwen I, Vandeweyer G, Boeckx N, Corneveaux JJ, van den Ende J, et al. DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System. Hum Mutat. 2016;37:812-9. doi: 10.1002/humu.22999. PubMed PMID: 27068579.
  24. Liu YT, Guo K, Li J, Liu Y, Zeng WH, Geng SM. Novel mutations in GJB6 and GJB2 in Clouston syndrome. Clin Exp Dermatol. 2015;40:770-3. doi: 10.1111/ced.12654. PubMed PMID: 25808784.
  25. Fujimoto A, Kurban M, Nakamura M, Farooq M, Fujikawa H, Kibbi AG, et al. GJB6, of which mutations underlie Clouston syndrome, is a potential direct target gene of p63. J Dermatol Sci. 2013;69:159-66. doi: 10.1016/j.jdermsci.2012.11.005. PubMed PMID: 23219093.
  26. Villanelo F, Escalona Y, Pareja-Barrueto C, Garate JA, Skerrett IM, Perez-Acle T. Accessing gap-junction channel structure-function relationships through molecular modeling and simulations. BMC Cell Biol. 2017;18:5. doi: 10.1186/s12860-016-0121-9. PubMed PMID: 28124624; PubMed Central PMCID: PMC5267332.
  27. Al Mughram MH, Catalano C, Herrington NB, Safo MK, Kellogg GE. 3D interaction homology: The hydrophobic residues alanine, isoleucine, leucine, proline and valine play different structural roles in soluble and membrane proteins. Front Mol Biosci. 2023;10:1116868. doi: 10.3389/fmolb.2023.1116868. PubMed PMID: 37056722; PubMed Central PMCID: PMC10086146.
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