The mutations in the GJB2 gene are the most common cause of nonsyndromic hearing impairment and they are associated with the population’s ethnic background. The p.Val27Ile is frequent in both Asia and America. In this retrospective study, we report the findings from the GJB2 screening and the audiological exams conducted on 125 Mexican mestizo patients with non-syndromic hearing impairment; they were treated at the Instituto Nacional de Rehabilitacion in Mexico City. The most frequent audiometric findings were bilateral, symmetrical, and profound hearing impairment. The allele frequencies in the GJB2 screening were p.Val27Ile 15%, other mutations 5%, and wild type 80%. We found no correlation between GJB2 genotype and auditory phenotype. The high allele frequency of p.Val27Ile was a very interesting finding. Our research suggests that p.Val27Ile arose in an ancient common ancestor who lived in Altai Republic and then the polymorphism was brought to America by its first inhabitants, the Amerindians. These results enhance our understanding of the peopling of the America, which remains unresolved. 1. Introduction The gap junction β2 gene (GJB2 [MIM*121011]) (Online Mendelian Inheritance in Man (OMIM), http://www.omim.org/), encoded to the protein connexin 26. Mutations in this gene are the most common cause of hereditary nonsyndromic hearing impairment, causing up to 50% of autosomal recessive cases [1, 2] and up to 37% of unknown cause [3]. Also, although infrequently, mutations in this gene cause genetic syndromes that affect hearing and skin [4, 5]. The frequency of GJB2 variants has been associated with ethnic background. The most frequent pathogenic mutations are c.35delG (p.Gly12ValfsTer1) in Caucasian Europeans [6], c.167delT (p.Leu56ArgfsTer26) in Ashkenazi Jews [7], c.427C>T (p.R143W) in Africans from Ghana [8], c.74G>A (p.W24X) in Indians and Romanies [9, 10], c.109G>A (p.V37Ile) in East Asians [11], and c.235delC (p.L79CfsX3) in East Asians (Japanese, Koreans, and Chinese), Mongolians (Central Asia), and southern Altaians (South Siberia) [12–16]. The high carrier frequencies (0.7 to 16%) of each of these pathogenic mutations among the populations in which they are endemic suggest that there may be some evolutionary advantage to being a carrier of these mutations [17]. The most frequent polymorphic variants are c.79G>A (p.Val27Ile) and c.341G>A (p.Glu114Gly); these are most frequent in East Asian populations [12–14, 18]. The p.Val27Ile polymorphism has been reported as the most common variant of GJB2 gene in several studies [12–16, 18–25]. It
References
[1]
P. Gasparini, X. Estivill, V. Volpini et al., “Linkage of DFNB1 to non-syndromic neurosensory autosomal-recessive deafness in Mediterranean families,” European Journal of Human Genetics, vol. 5, no. 2, pp. 83–88, 1997.
[2]
F. Denoyelle, D. Weil, M. A. Maw, et al., “Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene,” Human Molecular Genetics, vol. 6, no. 12, pp. 2173–2177, 1997.
[3]
X. Estivill, P. Fortina, S. Surrey et al., “Connexin-26 mutations in sporadic and inherited sensorineural deafness,” The Lancet, vol. 351, no. 9100, pp. 394–398, 1998.
[4]
D. P. Kelsell, W.-L. Di, and M. J. Houseman, “Connexin mutations in skin disease and hearing loss,” American Journal of Human Genetics, vol. 68, no. 3, pp. 559–568, 2001.
[5]
J. R. Lee and T. W. White, “Connexin-26 mutations in deafness and skin disease,” Expert Reviews in Molecular Medicine, vol. 11, p. e35, 2009.
[6]
L. Zelante, P. Gasparini, X. Estivill et al., “Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans,” Human Molecular Genetics, vol. 6, no. 9, pp. 1605–1609, 1997.
[7]
R. J. Morell, H. J. Kim, L. J. Hood, et al., “Mutations in the connexin 26 gene (GJB2) among Ashkenazi jews with nonsyndromic recessive deafness,” The New England Journal of Medicine, vol. 339, no. 21, pp. 1500–1505, 1998.
[8]
C. Hamelmann, G. K. Amedofu, K. Albrecht et al., “Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana,” Human Mutation, vol. 18, no. 1, pp. 84–85, 2001.
[9]
G. Minárik, V. Ferák, E. Feráková, A. Ficek, H. Poláková, and L. Kádasi, “High frequency of GJB2 mutation W24X among Slovak Romany (Gypsy) patients with non-syndromic hearing loss (NSHL),” General Physiology and Biophysics, vol. 22, no. 4, pp. 549–556, 2003.
[10]
M. RamShankar, S. Girirajan, O. Dagan, et al., “Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India,” Journal of Medical Genetics, vol. 40, no. 5, article e68, 2003.
[11]
D. K. Chan, I. Schrijver, and K. W. Chang, “Connexin-26-associated deafness: phenotypic variability and progression of hearing loss,” Genetics in Medicine, vol. 12, no. 3, pp. 174–181, 2010.
[12]
S. Abe, S.-I. Usami, H. Shinkawa, P. M. Kelley, and W. J. Kimberling, “Prevalent connexin 26 gene (GJB2) mutations in Japanese,” Journal of Medical Genetics, vol. 37, no. 1, pp. 41–43, 2000.
[13]
H.-J. Park, S. Houn Hahn, Y.-M. Chun, K. Park, and H.-N. Kim, “Connexin26 mutations associated with nonsyndromic hearing loss,” Laryngoscope, vol. 110, no. 9, pp. 1535–1538, 2000.
[14]
P. Dai, F. Yu, B. Han, et al., “GJB2 mutation spectrum in 2063 Chinese patients with nonsyndromic hearing impairment,” Journal of Translational Medicine, vol. 7, article 26, 2009.
[15]
M. Tekin, X.-J. Xia, R. Erdenetungalag et al., “GJB2 mutations in mongolia: complex alleles, low frequency, and reduced fitness of the deaf,” Annals of Human Genetics, vol. 74, no. 2, pp. 155–164, 2010.
[16]
O. Posukh, N. Pallarez-Ruiz, V. Tadinova, L. Osipova, M. Claustres, and A.-F. Roux, “First molecular screening of deafness in the Altai republic population,” BMC Medical Genetics, vol. 6, article 12, 2005.
[17]
D. K. Chan and K. W. Chang, “GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype,” The Laryngoscope, vol. 124, no. 2, pp. E34–E53, 2014.
[18]
H.-J. Kim, C.-H. Park, K.-O. Lee, et al., “Sequence variations and haplotypes of the GJB2 gene revealed by resequencing of 192 chromosomes from the general population in Korea,” Clinical and Experimental Otorhinolaryngology, vol. 3, no. 2, pp. 65–69, 2010.
[19]
A. Pandya, K. S. Arnos, X. J. Xia, et al., “Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands,” Genetics in Medicine, vol. 5, no. 4, pp. 295–303, 2003.
[20]
L. A. Shimmenti, A. Martínez, and M. Telatar, “Infant hearing loss and connexin testing in a diverse population,” Genetics in Medicine, vol. 10, no. 7, pp. 517–524, 2008.
[21]
M. L. Tamayo, M. Olarte, N. Gelvez et al., “Molecular studies in the GJB2 gene (Cx26) among a deaf population from Bogotá, Colombia: results of a screening program,” International Journal of Pediatric Otorhinolaryngology, vol. 73, no. 1, pp. 97–101, 2009.
[22]
M. L. Arenas-Sordo, I. Menendez, E. Hernández-Zamora, et al., “Unique spectrum of GJB2 mutations in Mexico,” International Journal of Pediatric Otorhinolaryngology, vol. 76, no. 11, pp. 1678–1680, 2012.
[23]
L. S. Castro, A. N. Marinho, E. M. Rodrigues, G. C. Marques, T. A. Carvalho, and S. E. Santos dos, “A study of GJB2 and delGJB6-D13S1830 mutations in Brazilian non- syndromic deaf children from the Amazon region,” Brazilian Journal of Otorhinolaryngology, vol. 79, pp. 95–99, 2013.
[24]
N. A. Barashkov, F. M. Teryutin, V. G. Pshennikova, et al., “Age-relate hearing impairment (ARHI) associated with GJB2 single mutation in the Yakut population isolate in Easter Siberia,” PLoS ONE, vol. 9, no. 6, Article ID e100848, 2014.
[25]
C. Paz-y-Mi？o, D. Beaty, A. López-Cortés, and I. Proa？o, “Frequency of GJB2 and del(GJB6-D13S1830) mutations among an Ecuadorian mestizo population,” International Journal of Pediatric Otorhinolaryngology, vol. 78, no. 10, pp. 1648–1654, 2014.
[26]
P. M. Kelley, D. J. Harris, B. C. Comer et al., “Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss,” The American Journal of Human Genetics, vol. 62, no. 4, pp. 792–799, 1998.
[27]
M. Tekin, T. Duman, G. Bo？o？lu et al., “Spectrum of GJB2 mutations in Turkey comprises both Caucasian and Oriental variants: roles of parental consanguinity and assortative mating,” Human Mutation, vol. 21, no. 5, pp. 552–553, 2003.
[28]
P. Hom？e, A. Koch, N. D. Rendtorff, et al., “GJB2 (Connexin-26) mutations are not frequent among hearing impaired patients in east Greenland,” International Journal of Audiology, vol. 51, no. 6, pp. 433–436, 2012.
[29]
A. C. Batissoco, R. S. Abreu-Silva, M. C. C. Braga, et al., “Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling,” Ear & Hearing, vol. 30, no. 1, pp. 1–7, 2009.
[30]
M. Arancibia, R. Ramírez, C. Farfán, M. Acu？a, and L. Cifuentes, “Frequency of the 35delG mutation of GJB2 (connexin 26) in a sample of deaf school children in Santiago,” Revista de Otorrinolaringología y Cirugía de Cabeza y Cuello, vol. 72, pp. 7–14, 2012.
[31]
V. Dalamón, A. Béhèran, F. Diamante, N. Pallares, V. Diamante, and A. B. Elgoyhen, “Prevalence of GJB2 mutations and the del(GJB6-D13S1830) in Argentinean non-syndromic deaf patients,” Hearing Research, vol. 207, no. 1-2, pp. 43–49, 2005.
[32]
J. Samanich, C. Lowes, R. Burk et al., “Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment,” American Journal of Medical Genetics A, vol. 143, no. 8, pp. 830–838, 2007.
[33]
G. Martínez-Cortés, J. Salazar-Flores, J. Haro-Guerrero et al., “Maternal admixture and population structure in Mexican-Mestizos based on mtDNA haplogroups,” American Journal of Physical Anthropology, vol. 151, no. 4, pp. 526–537, 2013.
[34]
B. Z. González-Sobrino, I. Silva-Zolessi, and L. Sebastián-Medina, “Estampas de Historia y Genética en México,” in Miradas sin rendición. Imaginario y presencia del universo indígena, S. Oria-Probert, Ed., pp. 52–56, Fideicomiso para la organización de la conmemoración del Bicentenario de la Independencia Nacional y Centenario de la Revolución Mexicana, Mexico City, Mexico, 1st edition, 2010.
[35]
A. Martini, M. Mazzoli, D. Stephens, and A. Read, Definitions Protocols and Guidelines in Genetic Hearing Impairment, Whurr Publisher, London, UK, 2001.
[36]
C. F. Martínez-Cruz, A. Poblano, and L. A. Fernández-Carrocera, “Risk factors associated with sensorineural hearing loss in infants at the neonatal intensive care unit: 15-year experience at the National Institute of Perinatology (Mexico City),” Archives of Medical Research, vol. 39, no. 7, pp. 686–694, 2008.
[37]
D. Gordon, C. Abajian, and P. Green, “Consed: a graphical tool for sequence finishing,” Genome Research, vol. 8, no. 3, pp. 195–202, 1998.
[38]
R. Cruz-Coke and R. S. Moreno, “Genetic epidemiology of single gene defects in Chile,” Journal of Medical Genetics, vol. 31, no. 9, pp. 702–706, 1994.
[39]
L. Gómez-Pérez, M. A. Alfonso-Sánchez, A. M. Pérez-Miranda et al., “Genetic admixture estimates by Alu elements in Afro-Colombian and Mestizo populations from Antioquia, Colombia,” Annals of Human Biology, vol. 37, no. 4, pp. 488–500, 2010.
[40]
S. D. Pena, G. di Pietro, M. Fuchshuber-Moraes, et al., “The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected,” PLoS ONE, vol. 6, no. 2, Article ID e17063, 2011.
[41]
D. Corach, O. Lao, C. Bobillo et al., “Inferring continental ancestry of argentineans from autosomal, Y-chromosomal and mitochondrial DNA,” Annals of Human Genetics, vol. 74, no. 1, pp. 65–76, 2010.
[42]
L. L. Cavalli-Sforza, Genes pueblos y lenguas, Crítica, Barcelona, Spain, 2010.
[43]
U. A. Perego, N. Angerhofer, M. Pala, et al., “The initial peopling of the Americas: a growing number of founding mitochondrial genomes from Beringia,” Genome Research, vol. 20, no. 9, pp. 1174–1179, 2010.
[44]
S. Wang, C. M. Lewis, M. Jakobsson et al., “Genetic variation and population structure in native Americans,” PLoS Genetics, vol. 3, no. 11, article e185, 2007.
[45]
L. L. Cavalli-Sforza and F. Cavalli-Sforza, Quienes somos? Historia de la diversidad humana, Crítica, Barcelona, Spain, 1994.
[46]
M. Livi-Bacci, Historia Mínima de la Población Mundial, Ariel, Barcelona, Spain, 1990.
[47]
H. F. Dobyns, “Disease transfer at contact,” Annual Review of Anthropology, vol. 22, pp. 273–291, 1993.
[48]
B. García-Martínez, “La época colonial hasta 1760,” in Nueva Historia mínima de México, P. Escalante-Gonzalbo, B. García Martínez, L. Jáuregui, J. Zoraida-Vázquez, E. Especkan-Guerra, and J. Garciadiego, Eds., p. 79, Colegio de México, Mexico City, Mexico, 2010.
[49]
V. N. Khar'kov, V. A. Stepanov, O. F. Medvedeva, et al., “Gene pool differences between Northern and Southern Altaians inferred from the data on Y-chromosomal haplogroups,” Genetika, vol. 43, no. 5, pp. 675–687, 2007.
[50]
I. A. Zakharov, M. V. Derenko, B. A. Maliarchuk, I. K. Dambueva, C. M. Dorzhu, and S. Y. Rychkov, “Mitochondrial DNA variation in the aboriginal populations of the Altai-Baikal region: implications for the genetic history of North Asia and America,” Annals of the New York Academy of Sciences, vol. 1011, pp. 21–35, 2004.
[51]
M. C. Dulik, S. I. Zhadanov, L. P. Osipova, et al., “Mitochondrial DNA and Y chromosome variation provides evidence for a recent common ancestry between Native Americans and Indigenous Altaians,” The American Journal of Human Genetics, vol. 90, no. 3, pp. 229–246, 2012.
[52]
L. L. Cavalli-Sforza, P. Menozzi, and A. Piazza, The History and Geography of Human Genes, Princeton University Press, Princeton, New Jersey, USA, 1994.
[53]
T. Goebel, “Pleistocene human colonization of Siberia and peopling of the Americas: an ecological approach,” Evolutionary Anthropology, vol. 8, no. 6, pp. 208–227, 1999.
[54]
F. R. Santos, A. Pandya, C. Tyler-Smith et al., “The central Siberian origin for native American Y chromosomes,” The American Journal of Human Genetics, vol. 64, no. 2, pp. 619–628, 1999.
[55]
M.-C. Bortolini, F. M. Salzano, M. G. Thomas et al., “Y-chromosome evidence for differing ancient demographic histories in the Americas,” American Journal of Human Genetics, vol. 73, no. 3, pp. 524–539, 2003.
[56]
J. H. Greenberg, Language in the Americas, Stanford University Press, Stanford, California, USA, 1987.
[57]
J. C. Chatters, D. J. Kennett, Y. Asmerom et al., “Late pleistocene human skeleton and mtDNA link paleoamericans and modern Native Americans,” Science, vol. 344, no. 6185, pp. 750–754, 2014.
[58]
B. Balci, F. ？zba？ Ger？eker, S. Aksoy et al., “Identification of an ancestral haplotype of the 35delG mutation in the GJB2 (connexin 26) gene responsible for autosomal recessive non-syndromic hearing loss in families from the Easter Black Sea region in Turkey,” Turkish Journal of Pediatrics, vol. 47, no. 3, pp. 213–221, 2005.
[59]
M. Tekin, G. Bo？o？lu, S. T. Arican, et al., “Evidence for single origins of 35delG and delE120 mutations in the GJB2 gene in Anatolia,” Clinical Genetics, vol. 67, no. 1, pp. 31–37, 2004.
[60]
L. Van Laer, P. Coucke, R. F. Mueller et al., “A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment,” Journal of Medical Genetics, vol. 38, no. 8, pp. 515–518, 2001.
[61]
H. Kokotas, M. Grigoriadou, M. Villamar, A. Giannoulia-Karantana, I. Del Castillo, and M. B. Petersen, “Hypothesizing an ancient greek origin of the GJB2 35delG mutation: can science meet history?” Genetic Testing and Molecular Biomarkers, vol. 14, no. 2, pp. 183–187, 2010.
[62]
L. U. Dzhelmileva, O. L. Posukh, N. A. Barashkov, et al., “Haplotype diversity and reconstruction of ancestral haplotype associated with the c.35delG mutation in the GJB2 (Cx26) gene among the Volgo-Ural populations of Russia,” Acta Naturae, vol. 3, no. 3, pp. 52–63, 2011.
[63]
D. Yan, H.-J. Park, X. M. Ouyang, et al., “Evidence of a founder effect for the 235delC mutation of GJB2 (connexin 26) in East Asians,” Human Genetics, vol. 114, no. 1, pp. 44–50, 2003.
[64]
L. U. Dzhemileva, N. A. Barashkov, O. L. Posukh et al., “Carrier frequency of GJB2 gene mutations c.35delG, c.235delC and c.167delT among the populations of Eurasia,” Journal of Human Genetics, vol. 55, no. 11, pp. 749–754, 2010.
[65]
M. Kretz, K. Maass, and K. Willecke, “Expression and function of connexins in the epidermis, analyzed with transgenic mouse mutants,” European Journal of Cell Biology, vol. 83, no. 11-12, pp. 647–654, 2004.
[66]
J. E. A. Common, W.-L. Di, D. Davies, and D. P. Kelsell, “Further evidence for heterozygote advantage of GJB2 deafness mutations: a link with cell survival,” Journal of Medical Genetics, vol. 41, no. 7, pp. 573–575, 2004.
[67]
S.-Y. Choi, K. Y. Lee, H.-J. Kim et al., “Functional evaluation of GJB2 variants in nonsyndromic hearing loss,” Molecular Medicine, vol. 17, no. 5-6, pp. 550–556, 2011.
