A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort

Putcha, Girish; Bejjani, Bassem A.; Bléoo, Stacey; Booker, Jessica K.; Carey, John C.; Carson, Nancy; Das, Soma; Dempsey, Melissa A; Gastier‐Foster, Julie M.; Greinwald, John H.; Hoffmann, Marcy L.; Jeng, Linda Jo Bone; Kenna, Margaret A.; Khababa, Ishrag; Lilley, Margaret; Mao, Rong; Muralidharan, Kasinathan; Otani, Iris M.; Rehm, Heidi L.; Schaefer, Fred; Seltzer, William; Spector, Elaine; Springer, Michelle; Weck, Karen E.; Wenstrup, Richard J.; Withrow, Stacey; Wu, Bai Lin; Zariwala, Maimoona A.; Schrijver, Iris

doi:10.1097/gim.0b013e3180a03276

Cited by 130 publications

(108 citation statements)

References 63 publications

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“…21 The absence of any deletions in our cholesteatoma population is consistent with this low carrier rate, and seems to exclude the possibility that GJB6 deletions contribute to cholesteatoma formation by modification of GJB2 expression.…”

Section: Discussionsupporting

confidence: 49%

Pediatric cholesteatoma and variants in the gene encoding connexin 26

et al. 2009

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Objectives/Hypothesis: Connexin 26 is a gap junction protein encoded by the GJB2 gene. It is expressed in cholesteatoma, and mutations cause proliferative skin disorders and sensorineural hearing loss (SNHL). Deletions of GJB6, which encodes connexin 30, cause SNHL in a digenic manner with a heterozygous GJB2 mutation. We hypothesize that GJB2 and GJB6 mutations might influence the development of cholesteatoma.Study Design: Prospective observational study to identify GJB mutations in pediatric cholesteatoma.Methods: Peripheral blood samples from 98 children with cholesteatoma were screened for mutations in the GJB2 gene by direct sequencing of the coding region (exon 2 and the intron/exon boundary). Deletions of the GJB6 gene were tested using multiple ligation probe amplification methods. GJB status was compared with other populations and patient age and extent of cholesteatoma at presentation.Results: Fourteen children had at least one GJB2 variant (14%). Of these, three had two variants. Two of the variants were neutral polymorphisms. One child with the GJB2 genotype 35delG/35delG also had SNHL. No correlation was found between GJB2 status and patient age or cholesteatoma severity at presentation. No GJB6 deletions were found.Conclusions: GJB2 gene variants are present in a minority of children with cholesteatoma, but may be more common than in normal populations. It is conceivable that alterations of connexin 26 expression could contribute to the multifactorial disease process in cholesteatoma by modifying the cell-to-cell communication that is important in proliferation and migration of keratinocytes.

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Section: Discussionsupporting

confidence: 49%

Pediatric cholesteatoma and variants in the gene encoding connexin 26

et al. 2009

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“…Meanwhile, nongenetic and genetic factors were found to almost equally contribute to the etiology of hearing loss in children (8). As genetic factors, the mutations of the gap junction β-2 (GJB2) gene were considered an important cause of SNHL (9)(10)(11)(12). Studies indicate that congenital CMV infection may cause chromosome aberrations, including selective chromosome breakages, chromosome pulverization, premature chromatid condensation, and structural injury to the centrosome (13)(14)(15)(16)(17)(18), e.g., genetic damages on 1q23.3 (14), 1q21, and 1q42 (17).…”

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confidence: 99%

Does congenital cytomegalovirus infection lead to hearing loss by inducing mutation of the GJB2 gene?

Li¹,

Tan²,

Zhou³

et al. 2013

Pediatr Res

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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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“…Although some hearing impaired patients would be expected to be GJB2 carriers by chance, the cumulative data support the existence of additional, as yet unknown, mutations at the DFNB1 locus. Alternatively, it is possible that carriers of recessive mutations in GJB2 are at an increased risk for hearing loss from other causes [Estivill et al, 1998;Green et al, 1999;Roux et al, 2004;Tang et al, 2006;Putcha et al, 2007]. The observations of this and prior studies suggest that further investigation of the DFNB1 locus is needed.…”

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confidence: 77%

“…It is curious that prior studies have consistently demonstrated larger than expected numbers of heterozygous GJB2 mutation carriers in patient cohorts [Estivill et al, 1998;Green et al, 1999;Roux et al, 2004;Hutchin et al, 2005;Tang et al, 2006;Putcha et al, 2007]. Although some hearing impaired patients would be expected to be GJB2 carriers by chance, the cumulative data support the existence of additional, as yet unknown, mutations at the DFNB1 locus.…”

mentioning

confidence: 99%