Abstract
Connexin 26 (Cx-26), a gap junction protein coded by GJB2 gene, plays a very important role in recycling of potassium ions, one of the vital steps in the mechanotransduction process of hearing. Mutations in the GJB2 gene have been associated with both autosomal recessive as well as dominant nonsyndromic hearing loss. As Cx-26 is linked with skin homeostasis, mutations in this gene are sometimes associated with syndromic forms of hearing loss showing skin anomalies. We report here a non consanguineous assortatively mating hearing impaired family with one of the hearing impaired partners, their hearing impaired sibling and hearing impaired offspring showing compound heterozygosity in the GJB2 gene, involving a dominant mutation p.R184Q and two recessive mutations p.Q124X and c.IVS 1+1G>A in a unique triallelic combination. To the best of our knowledge, this is the first report from India on p.R184Q mutation in the GJB2 gene associated with rare compound heterozygosity showing nonsyndromic presentation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Hilgert N, Smith RJ, Van Camp G (2009) Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics. Mutat Res 681:189–196
Mehl AL, Thomson V (1998) Newborn hearing screening: the great omission. Pediatrics 101(E1):1–6
Morton CC, Nance WE (2006) Newborn hearing screening—a silent revolution. N Engl J Med. 354:2151–2164
Marazita ML, Ploughman LM, Rawlings B, Remington E, Arnos KS, Nance WE (1993) Genetic epidemiological studies of early-onset deafness in the US school-age population. Am J Med Genet 46:486–491
Toriello HV, Reardon W, Gorlin RJ (2004) Hereditary hearing loss and its syndromes. Oxford University Press, New York
Smith RJ, Bale JF Jr, White KR (2005) Sensorineural hearing loss in children. Lancet 365:879–890
Kenneson A, Van Naarden BK, Boyle C (2002) GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med. 4:258–274
Snoeckx RL et al (2005) GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet 77:945–957
Yum SW, Zhang J, Scherer SS (2010) Dominant connexin26 mutants associated with human hearing loss have trans-dominant effects on connexin30. Neurobiol Dis 38(2):226–236
Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryynänen M et al (2002) Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis- ichthyosis-deafness syndrome. Am J Hum Genet 70:1341–1348
Martin PEM, Evans HW (2004) Incorporation of connexins into plasma membranes and gap junctions. Cardiovasc Res 62:378–387
Hamelmann C, Amedofu GK, Albrecht K, Muntau B, Gelhaus A, Brobby GW et al (2001) Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana. Hum Mutat 18:84–85
Pavithra A, Selvakumari M, Nityaa V, Sharanya N, Ramakrishnan R, Narasimhan M et al (2015) Autosomal dominant hearing loss resulting from p.R75Q mutation in the GJB2 gene: nonsyndromic presentation in a South Indian family. Ann Hum Genet 79(1):76–82
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, New York
RamShankar M, Girirajan S, Dagan O, Ravi Shankar HM, Jalvi R, Rangasayee R et al (2003) Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India. J Med Genet 40:e68
del Castillo FJ, Rodríguez-Ballesteros M, Álvarez A et al (2005) 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 42:588–594
Del Castillo I, Villamar M, Moreno-Pelayo MA, del Castillo FJ, Alvarez A, Telleria D et al (2002) A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. N Engl J Med 346:243–249
Su CC, Li SY, Su MC, Chen WC, Yang JJ (2010) Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30. Eur J Hum Genet 18:1061–1064
Welch KO, Marin RS, Pandya A, Arnos KS (2007) Compound heterozygosity for dominant and recessive GJB2 mutations: effect on phenotype and review of the literature. Am J Med Genet 143A:1567–1573
Titeux M, Mendonça V, Decha A, Moreira E, Magina S, Maia A et al (2009) Keratitis–ichthyosis–deafness syndrome caused by GJB2 maternal mosaicism. J Investig Dermatol 129:776–779
Sbidian E, Feldmann D, Bengoa J, Fraitag S, Abadie V, de Prost Y et al (2010) Germline mosaicism in keratitis–ichthyosis–deafness syndrome: pre-natal diagnosis in a familial lethal form. Clin Genet 77(6):587–592
Rouan F, White TW, Brown N, Taylor AM, Lucke TW, Paul DL et al (2001) Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. J Cell Sci 114:2105–2113
Wang YC et al (2002) Mutations of Cx26 gene (GJB2) for prelingual deafness in Taiwan. Eur J Hum Genet 10:495–498
Yang JJ et al (2007) Identification of mutations in members of the connexin gene family as a cause of nonsyndromic deafness in Taiwan. Audiol Neuro otol 12:198–208
Yaeger D et al (2006) Outcomes of clinical examination and genetic testing of 500 individuals with hearing loss evaluated through a genetics of hearing loss. Clin Am J Med Genet 140A:827–836
Mahdieh N et al (2010) Unexpected heterogeneity due to recessive and de novo dominant mutations of GJB2 in an Iranian family with nonsyndromic hearing loss: implication for genetic counseling. Biochem Biophys Res Commun 402:305–307
Huang S et al (2011) De novo dominant mutation of GJB2 in two Chinese families with nonsyndromic hearing loss. Int J Pediatr Otorhinolaryngol 75:1333–1336
Weegerink NJ et al (2011) Phenotypes of two Dutch DFNA3 families with mutations in GJB2. Ann Otol Rhinol Laryngol 120:191–197
de la Luz Arenas-Sordo M et al (2012) Unique spectrum of GJB2 mutations in Mexico. Int J Pediatr Otorhinolaryngol 76:1678–1680
Minarik G et al (2012) Prevalence of DFNB1 mutations in Slovak patients with non-syndromic hearing loss. Int J Pediatr Otorhinolaryngol 76:400–403
Pang X et al (2014) Characterization of spectrum, de novo rate and genotype–phenotype correlation of dominant GJB2 mutations in Chinese hans. PLoS One 9:e100483
Loffler J et al (2001) Sensorineural hearing loss and the incidence of Cx26 mutations in Austria. Eur J Hum Genet 9:226–230
Bonyadi M et al (2009) Mutation analysis of familial GJB2-related deafness in Iranian Azeri Turkish patients. Genet Test Mol Biomark 13:689–692
Riahi Z et al (2013) Compound heterozygosity for dominant and recessive GJB2 mutations in a Tunisian family and association with successful cochlear implant outcome. Int J Pediatr Otorhinolaryngol 77:1481–1484
Acknowledgments
We are grateful to the family for their cooperation and participation in this study. This study was supported by the Ad hoc Research Project of the Indian Council of Medical Research (ICMR), Government of India, to C. R. Srikumari Srisailapathy and the Special Assistance Program-DRS II of University Grants Commission (UGC) to the Department of Genetics. A. Pavithra was a Senior Research Fellow of the ICMR Ad hoc Research project. J. Chandru was supported by a Senior Research Fellowship from UGC for Basic Scientific Research. J. M. Jeffrey was a Research Fellow of UGC-UPE-II-Biomedical Research Project.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Pavithra, A., Chandru, J., Jeffrey, J.M. et al. Rare compound heterozygosity involving dominant and recessive mutations of GJB2 gene in an assortative mating hearing impaired Indian family. Eur Arch Otorhinolaryngol 274, 119–125 (2017). https://doi.org/10.1007/s00405-016-4229-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00405-016-4229-5