A Deletion Involving the Connexin 30 Gene in Nonsyndromic Hearing Impairment

Castillo, Ignacio del; Villamar, Manuela; Moreno-Pelayo, Miguel A.; Castillo, Francisco; Álvarez, A. Fernández; Tellerı́a, Dolores; Menéndez, Ibis; Moreno, Felipe

doi:10.1056/nejmoa012052

Cited by 518 publications

(502 citation statements)

References 29 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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“…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%

“…This deletion was the second most frequent connexin mutation reported for NSHI in Spain, France, Israel, Great Britain and Brazil [20,25]. Individuals who are either homozygous for del(GJB6-D13S1830) or compound heterozygotes of del(GJB6-D13S1830) and a mutant allele of GJB2 develop NSHI, resulting in profound to severe HI [26].…”

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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“…The 309 kb deletion involving GJB6 [Lerer et al, 2001;Pallares-Ruiz et al, 2002;del Castillo et al, 2002] was observed only once, in a patient of unknown ethnicity who is heterozygous for a p.Gln57X (p.Q57X) mutation in GJB2 (data not shown). In this patient, detection of heterozygous mutations in GJB2 and GJB6 supports an etiologic diagnosis of DFNB1-associated hereditary hearing loss.…”

mentioning

confidence: 95%

“…It is likely that founder effects, population stratification, and assortative mating at least partially explain the variable frequency of these deletions in different populations [Lerer et al, 2001;Pallares-Ruiz et al, 2002;del Castillo et al, 2002;Fitzgerald et al, 2004;Gualandi et al, 2004;Roux et al, 2004;Dalamon et al, 2005;Del Castillo et al, 2005;Seeman et al, 2005].…”

mentioning

confidence: 99%

Infrequency of two deletion mutations at the DFNB1 locus in patients and controls

Tang

Basehore

Blakey

et al. 2008

American J of Med Genetics Pt A

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A Deletion Involving the Connexin 30 Gene in Nonsyndromic Hearing Impairment

Cited by 518 publications

References 29 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

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

Infrequency of two deletion mutations at the DFNB1 locus in patients and controls

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