Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus

Grifa, A.; Wagner, Carsten A.; D’Ambrosio, Luigi; Melchionda, Salvatore; Bernardi, Francesco; López‐Bigas, Núria; Rabionet, Raquel; Arbonés, Mariona; Monica, Matteo Della; Estivill, Xavier; Zelante, Leopoldo; Läng, Florian; Gasparini, Paolo

doi:10.1038/12612

Cited by 360 publications

(257 citation statements)

References 14 publications

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“…The most frequent causative gene for nonsyndromatic SNHL is GJB2 ( CX26 ) (Smith et al, 2014 2014). Although less frequent, mutations in GJB6 ( CX30 ) (Grifa et al, 1999; del Castillo et al, 2002) and GJA1 (CX43) (Liu et al, 2001; Hong et al, 2010) have also been linked to SNHL. These gap junction proteins are thought to play a role in maintaining cochlear ion homeostasis and the endocochlear potential, as shown in Gjb6 ‐deficient mice (Teubner et al, 2003), by passively recycling K + ions back to the stria vascularis.…”

Section: Discussionmentioning

confidence: 99%

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

Locher

Groot

Iperen

et al. 2015

Developmental Neurobiology

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Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9–W18) and show the cochlear expression dynamics of key potassium‐regulating proteins. At W12, MITF+/SOX10+/KIT+ neural‐crest‐derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na+/K+‐ATPase‐positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1219–1240, 2015

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Section: Discussionmentioning

confidence: 99%

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

Locher

Groot

Iperen

et al. 2015

Developmental Neurobiology

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“…This implies that a loss of GJB2 expression through disruption of cis-regulatory elements, and not a digenic interaction between GJB2 and GJB6, is the underlying mechanism causing hearing loss due to these deletions. 42,43 Therefore, despite the moderate evidence associating missense variants in GJB6-namely, Gly11Arg and Ala88Val, NM_006783.4-with autosomal-dominant hidrotic ectodermal dysplasia (Clouston syndrome; OMIM 129500), 44 the evidence associating sequence variants in this gene with autosomaldominant or digenic (with GJB2) nonsyndromic hearing loss 45,46 remains questionable given the limited segregation and functional evidence for reported variants. In summary, it remains to be determined whether variants affecting the function or expression of GJB6 are causative for hearing loss.…”

Section: Examples Of Genes With No or Weak Associationmentioning

confidence: 99%

Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing–based diagnostic testing and interpretation

Tayoun

Turki

Oza

et al. 2016

Genetics in Medicine

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“…and GJB6 present at this locus encoding the proteins connexin 26 (Cx26) and connexin 30 (Cx30) [18][19][20]. Some 111 mutations associated with NSHI have been described in GJB2, of which 92 have an autosomal recessive (AR) mode of inheritance, nine are inherited as autosomal dominant (AD) mutations, and 10 others have no clearly defined pattern of transmission [17].…”

Section: Introductionmentioning

confidence: 99%

Non-syndromic hearing impairment in a multi-ethnic population of Northeastern Brazil

Manzoli

Abe‐Sandes

Bittles

et al. 2013

International Journal of Pediatric Otorhinolaryngology

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SUMMARYObjective: There are many hearing impaired individuals in Monte Santo, a rural municipality in the state of Bahia, Brazil, including multiple familial cases strongly suggestive of a genetic aetiology.Methods: The present study investigated 81 subjects with hearing impairment (HI) recruited from 36 families. Mutations previously associated with HI were initially analyzed: c.35delG in gene GJB2, del(GJB6-D13S1830) and del(GJB6-D13S1854) in gene GJB6, and A1555G in the mitochondrial gene MTRNR1, with additional mutations in GJB2 identified by sequencing the coding region of the gene.Results: Seven different mutations were present in GJB2 with mutations c.35delG and p.R75Q, which are known to be pathogenic, identified in 37.0% of the subjects. Individuals homozygous for the c.35delG mutation were diagnosed in eight families, corresponding to 24.6% of unrelated individuals with nonsyndromic hearing impairment (NSHI), and an additional heterozygote for this mutation was present in a single family. Ten individuals (12.4%) in another family were heterozygous for the mutation p.R75Q. Conclusions:Significant heterogeneity was observed in the alleles and patterns of NSHI inheritance among the subjects studied, probably due to the extensive inter-ethnic admixture that characterizes the peoples of Brazil, and a high prevalence of community endogamy and consanguineous marriage.

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Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus

Cited by 360 publications

References 14 publications

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing–based diagnostic testing and interpretation

Non-syndromic hearing impairment in a multi-ethnic population of Northeastern Brazil

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