Abstract
Background:
Congenital cytomegalovirus (CMV) infection and mutation of the gap junction β-2 (GJB2) gene are important causes of sensorineural hearing loss (SNHL). This study aims to determine if congenital CMV infection leads to deafness by inducing GJB2 mutation.
Methods:
GJB2 gene sequencing and auditory brainstem response testing were performed in 159 neonates (63 with and 96 without CMV infection) from August 2008 to August 2011. For neonates with GJB2 mutation, their parents were further screened for GJB2 sequence.
Results:
The incidence of SNHL was 12.7% in CMV-infected but 0% in uninfected children aged 1–1.5 y (P = 0.000). Similar mutation rates of the GJB2 gene were observed in neonates with or without CMV infection (34.9 vs. 32.3%, respectively, P = 0.734). No significant difference in the mutation rate of GJB2 was found among neonates with CMV infection and SNHL, those with CMV infection and normal hearing, and uninfected newborns with normal hearing (P = 0.438). Mutations 79G>A, 109G>A, 341A>G, and 608T>C were found in neonates with and without CMV infection. All of the above mutations were also found in both or one of the corresponding parents.
Conclusion:
Congenital CMV infections may cause deafness in neonates, but this might be independent of GJB2 gene mutation.
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References
Morton CC, Nance WE . Newborn hearing screening: a silent revolution. N Engl J Med 2006;354:2151–64.
Boppana SB, Rivera LB, Fowler KB, Mach M, Britt WJ . Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med 2001;344:1366–71.
Nance WE, Lim BG, Dodson KM . Importance of congenital cytomegalovirus infections as a cause for pre-lingual hearing loss. J Clin Virol 2006;35:221–5.
Fowler KB, Boppana SB . Congenital cytomegalovirus (CMV) infection and hearing deficit. J Clin Virol 2006;35:226–31.
Dahle AJ, Fowler KB, Wright JD, Boppana SB, Britt WJ, Pass RF . Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus. J Am Acad Audiol 2000;11:283–90.
Schachtele SJ, Mutnal MB, Schleiss MR, Lokensgard JR . Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice. J Neurovirol 2011;17:201–11.
Cekinovic D, Golemac M, Pugel EP, et al. Passive immunization reduces murine cytomegalovirus-induced brain pathology in newborn mice. J Virol 2008;82:12172–80.
Kochhar A, Hildebrand MS, Smith RJ . Clinical aspects of hereditary hearing loss. Genet Med 2007;9:393–408.
Putcha GV, Bejjani BA, Bleoo S, et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med 2007;9:413–26.
Mistrík P, Ashmore JF . Reduced electromotility of outer hair cells associated with connexin-related forms of deafness: an in silico study of a cochlear network mechanism. J Assoc Res Otolaryngol 2010;11:559–71.
Beltramello M, Piazza V, Bukauskas FF, Pozzan T, Mammano F . Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness. Nat Cell Biol 2005;7:63–9.
Forge A, Becker D, Casalotti S, et al. Gap junctions and connexin expression in the inner ear. Novartis Found Symp 1999;219:134–50; discussion 151–6.
Fortunato EA, Spector DH . Viral induction of site-specific chromosome damage. Rev Med Virol 2003;13:21–37.
Nystad M, Fagerheim T, Brox V, Fortunato EA, Nilssen Ø . Human cytomegalovirus (HCMV) and hearing impairment: infection of fibroblast cells with HCMV induces chromosome breaks at 1q23.3, between loci DFNA7 and DFNA49 – both involved in dominantly inherited, sensorineural, hearing impairment. Mutat Res 2008;637:56–65.
Bystrevskaya VB, Lobova TV, Smirnov VN, Makarova NE, Kushch AA . Centrosome injury in cells infected with human cytomegalovirus. J Struct Biol 1997;120:52–60.
Siew VK, Duh CY, Wang SK . Human cytomegalovirus UL76 induces chromosome aberrations. J Biomed Sci 2009;16:107.
Fortunato EA, Dell’Aquila ML, Spector DH . Specific chromosome 1 breaks induced by human cytomegalovirus. Proc Natl Acad Sci USA 2000;97:853–8.
Kelley PM, Harris DJ, Comer BC, et al. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet 1998;62:792–9.
Ogawa H, Suzutani T, Baba Y, et al. Etiology of severe sensorineural hearing loss in children: independent impact of congenital cytomegalovirus infection and GJB2 mutations. J Infect Dis 2007;195:782–8.
Ross SA, Novak Z, Kumbla RA, Zhang K, Fowler KB, Boppana S . GJB2 and GJB6 mutations in children with congenital cytomegalovirus infection. Pediatr Res 2007;61:687–91.
Misono S, Sie KC, Weiss NS, et al. Congenital cytomegalovirus infection in pediatric hearing loss. Arch Otolaryngol Head Neck Surg 2011;137:47–53.
Grosse SD, Ross DS, Dollard SC . Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing loss: a quantitative assessment. J Clin Virol 2008;41:57–62.
Ross SA, Fowler KB, Ashrith G, et al. Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity. J Pediatr 2006;148:332–6.
Tsutsui Y . Effects of cytomegalovirus infection on embryogenesis and brain development. Congenit Anom (Kyoto) 2009;49:47–55.
Priya K, Madhavan HN . Diagnostic value of enzyme linked immuno-sorbent assay for cytomegalovirus disease. J Postgrad Med 2002;48:176–8; discussion 190.
Ross SA, Novak Z, Fowler KB, Arora N, Britt WJ, Boppana SB . Cytomegalovirus blood viral load and hearing loss in young children with congenital infection. Pediatr Infect Dis J 2009;28:588–92.
Boppana SB, Fowler KB, Pass RF, et al. Congenital cytomegalovirus infection: association between virus burden in infancy and hearing loss. J Pediatr 2005;146:817–23.
Lanari M, Lazzarotto T, Venturi V, et al. Neonatal cytomegalovirus blood load and risk of sequelae in symptomatic and asymptomatic congenitally infected newborns. Pediatrics 2006;117:e76–83.
Walter S, Atkinson C, Sharland M, et al. Congenital cytomegalovirus: association between dried blood spot viral load and hearing loss. Arch Dis Child Fetal Neonatal Ed 2008;93:F280–5.
Devdariani T, Gogberashvili K, Manjavidze N, Kamkamidze G . Association between the cytomegalovirus seroprevalence and hearing loss in early childhood. Georgian Med News 2011;195:61–5.
McMullan BJ, Palasanthiran P, Jones CA, et al. Congenital cytomegalovirus–time to diagnosis, management and clinical sequelae in Australia: opportunities for earlier identification. Med J Aust 2011;194:625–9.
Boppana SB, Ross SA, Shimamura M, et al.; National Institute on Deafness and Other Communication Disorders CHIMES Study. Saliva polymerase-chain-reaction assay for cytomegalovirus screening in newborns. N Engl J Med 2011;364:2111–8.
Bankier AT, Beck S, Bohni R, et al. The DNA sequence of the human cytomegalovirus genome. DNA Seq 1991;2:1–12.
Berg AL, Prieve BA, Serpanos YC, Wheaton MA . Hearing screening in a well-infant nursery: profile of automated ABR-fail/OAE-pass. Pediatrics 2011;127:269–75.
Rosenthal LS, Fowler KB, Boppana SB, et al. Cytomegalovirus shedding and delayed sensorineural hearing loss: results from longitudinal follow-up of children with congenital infection. Pediatr Infect Dis J 2009;28:515–20.
Smith RJ, Bale JF Jr, White KR . Sensorineural hearing loss in children. Lancet 2005;365:879–90.
Fowler KB, McCollister FP, Dahle AJ, Boppana S, Britt WJ, Pass RF . Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr 1997;130:624–30.
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Li, LQ., Tan, JJ., Zhou, Y. et al. Does congenital cytomegalovirus infection lead to hearing loss by inducing mutation of the GJB2 gene?. Pediatr Res 74, 121–126 (2013). https://doi.org/10.1038/pr.2013.77
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DOI: https://doi.org/10.1038/pr.2013.77