Connexin 26 Gene Mutations in Congenitally Deaf Children

Marlin, Sandrine; Garabédian, Éréa-Noël; Roger, Gilles; Moatti, L; Matha, N.; Lewin, Patricia; Petit, Christine; Denoyelle, Françoise

doi:10.1001/archotol.127.8.927

Cited by 118 publications

(124 citation statements)

References 26 publications

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“…Note that patients associated with 235delC show relatively severer hearing loss whereas V37I-involved patients show a relatively mild phenotype. It is also evident that patients associated with inactivating mutation/inactivating mutation showed a severer phenotype than patients with noninactivating mutation/ noninactivating mutation 35delG exhibit severe-to-profound hearing impairment (Cohn et al 1999;Cryns et al 2004;Denoyelle et al 1997Denoyelle et al , 1999Green et al 1999;Marlin et al 2001;Wilcox et al 2000). The status of the 235delC mutation, which seems to be a unique mutation in populations with Asian ancestry, is comparable to the 35delG mutation in Caucasoid populations.…”

Section: Discussionmentioning

confidence: 99%

“…Several reports have indicated the existence of lesssevere phenotypes correlated with certain specific mutations, especially in association with V37I (Bason et al 2002;Cryns et al 2004;Marlin et al 2001;Rabionet et al 2000;Wilcox et al 2000). The exact phenotype has been rather difficult to prove because of the relatively small number of patients with V37I.…”

Section: Discussionmentioning

confidence: 99%

“…The exact phenotype has been rather difficult to prove because of the relatively small number of patients with V37I. The V37I mutation was originally reported as a polymorphism (Kelley et al 1998), but the fact that valine 37 residue is highly conserved among different connexins, and that a series of reports identified homozygous or compound heterozygous V37I deafness patients (Abe et al 2000;Bason et al 2002;Marlin et al 2001;Rabionet et al 2000;Wilcox et al 2000), indicate that it may be a disease-causing mutation. There seem to be ethnic differences in the allele frequency of V37I, as it was not detected in the control subjects from Italy, Spain, Germany, Greece, Israel, Ghana, or Austria (see Discussion in Bason et al 2002) in spite of a high prevalence in the Japanese population (Abe et al 2000;Kudo et al 2000;Ohtsuka et al 2003).…”

Section: Discussionmentioning

confidence: 99%

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Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns

et al. 2005

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Mutations in the GJB2 (connexin 26, Cx26) gene are the major cause of nonsyndromic hearing impairment in many populations. Genetic testing offers opportunities to determine the cause of deafness and predict the course of hearing, enabling the prognostication of language development. In the current study, we compared severity of hearing impairment in 60 patients associated with biallelic GJB2 mutations and assessed the correlation of genotypes and phenotypes. Within a spectrum of GJB2 mutations found in the Japanese population, the phenotype of the most prevalent mutation, 235delC, was found to show more severe hearing impairment than that of V37I, which is the second most frequent mutation. The results of the present study, taken together with phenotypes caused by other types of mutations, support the general rule that phenotypes caused by the truncating GJB2 mutations are more severe than those caused by missense mutations. The present in vitro study further confirmed that differences in phenotypes could be explained by the protein expression pattern.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns

et al. 2005

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“…14 -16 However, others and we have reported normal hearing subjects carrying a compound heterozygous mutation:M34T/ 35delG. 10,17 Furthermore, Cucci et al 18 argue that the M34T allele variant may be dependent on the mutations segregating in the opposite allele. The M34T substitution was also implicated in the phenotypic expression of association of a palmoplantar keratoderma (PPK) with deafness 7 (MIM 124500).…”

Section: Introductionmentioning

confidence: 88%

Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene

et al. 2003

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Mutations in GJB2 are the most common cause of congenital nonsyndromic hearing loss. The controversial allele variant M34T has been hypothesized to cause autosomal dominant or recessive nonsyndromic hearing impairment and some in vitro data has been consistent with this hypothesis. In this report, we present the clinical and genotypic study of 11 families (seven familial forms of nonsyndromic sensorineural hearing loss (NSSNHL) and four sporadic cases) in which the M34T GJB2 variant has been identified. The M34T mutation did not segregate with the deafness in six of the seven familial forms of NSSNH. Eight persons with normal audiogram presented a heterozygous M34T variation and five normal hearing individuals were composite heterozygous for M34T and another GJB2 mutation. Four normal hearing individuals with a documented audiogram were M34T/35delG and one was M34T/(GJB6-D13S1830)del. Screening a French control population of 116 subjects we have found an M34T allele frequency of 1.72%. This percentage was not significatively different from the prevalence of the M34T allele in the deaf population, which was 2.12%. All these data suggest that the M34T variant is not clinically significant in human and is a frequent polymorphism in France.

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“…Analysis of microsatellite markers spanning the GJB2 region was carried out to substantiate the apparent cosegregation between mutation and phenotype (Fig. 2) This mutation was described as a polymorphism not related to the disease as it was detected in combination with c.35delG on the other allele in individuals with normal hearing (Marlin et al, 2001). In hearing impaired patients, c.380G>A (R127H) was found to be present without a second mutation on the other allele and therefore not classified as a non-pathogenic DNA change (Estivill et al, 1998.…”

Section: Table1: Summary Of Gjb2 Sequence Variants Detected In Hungarmentioning

confidence: 99%

GJB2mutations in patients with non-syndromic hearing loss from Northeastern Hungary

Tóth¹,

Kupka²,

Haack³

et al. 2004

Hum. Mutat.

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These authors contributed equally to this work. Communicated by Mark H. PaalmanMutations in the GJB2 gene encoding the gap-junction protein connexin 26 have been identified in many patients with childhood hearing impairment (HI). One single mutation, c.35delG, accounts for the majority of mutations in Caucasian patients with HI. In the present study we screened 500 healthy control individuals and a group of patients with HI from Northeastern Hungary for GJB2 mutations. The patients' group consisted of 102 familial from 28 families and 92 non-familial cases. The most common mutation in the Hungarian population is the c.35delG, followed by the c.71G>A (p.W24X) mutation. 34.3% of the patients in the familial group were homozygous, and 17.6% heterozygous for 35delG. In the non-familial group the respective values were 37% and 18% (allele frequency: 46.2%). In the general population an allele frequency of 2.4% was determined. Several patients were identified with additional, already described or new GJB2 mutations, mostly in heterozygous state. The mutation c.380G>A (p.R127H) was formerly found only in heterozygous state and its disease relation was controversial. We demonstrated the presence of this mutation in a family with three homozygous patients and 4 heterozygous unaffected family members, a clear indication of recessively inherited HI. Furthermore, we provided evidence for the pathogenic role of two new mutations, c.51C>A (p.S17Y) and c.177G>T (p.G59V), detected in the present study. In the latter case the pattern of inheritance might be dominant. Our results confirm the importance of GJB2 mutations in the Hungarian population displaying mutation frequencies that are comparable with those in the Mediterranean area.

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Connexin 26 Gene Mutations in Congenitally Deaf Children

Abstract: Interpretation of results for the molecular diagnosis of mutations in the connexin 26 gene is difficult in almost one third of cases. Close collaboration between geneticists familiar with deafness and otolaryngologists is essential to provide a high standard of genetic advice.

Cited by 118 publications

References 26 publications

Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns

Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns

Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene

GJB2mutations in patients with non-syndromic hearing loss from Northeastern Hungary

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