Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss

Houseman, M; Ellis, Lucy; Pagnamenta, Alistair T.; Di, Wei‐Li; Rickard, Sarah; Osborn, Amelia H.; Dahl, Hans‐Henrik M.; Taylor, Graham R.; Bitner‐Glindzicz, Maria; Mueller, Robert F.; Kelsell, David P.

doi:10.1136/jmg.38.1.20

Cited by 77 publications

(92 citation statements)

References 25 publications

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“…The frequency of the M34T allele in the French control population reported here (1.72%) is consistent with prevalence found in other populations: 25 1.5% in the USA, 8 2.4% in Belgium, 26 1.98% in the UK, 11 1.33% in the Grampian region. 27 In another way, this variant seems to be rare in Asia.…”

Section: Discussionsupporting

confidence: 75%

“…12,11,18,10,23,13,24 However, as Griffith et al 10 we reported here five normal hearing subjects carrying a compound heterozygous mutation in which the M34T substitution is associated in trans with a truncated mutation : the 35delG GJB2 mutation or the (GJB6-D13S1830)del. 20 These results indicate that M34T is not a recessive mutation responsible for hearing loss.…”

Section: Discussionmentioning

confidence: 58%

“…Two recent reports have found a 10 base pairs deletion in the 5 0 UTR of GJB2 that occurs together with the M34T mutation. 11,24 The last one 24 have demonstrated a linkage desequilibrum between these two variants. However, in several families reported in these two studies, 11,24 neither the M34T nor the À493del10 segregated with the deafness.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of deaf patients homozygous for the M34T variant, as in our report (family no. 7) and in others, 11,24 should not be considered as an argument for the pathogenicity of this variant because if M34T is a frequent polymorphism, it could be fortuitously present in a homozygous state in some patients.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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“…However, the M34T allele was sometimes found as a compound heterozygote among individuals with hearing loss, 7,30,34,39,46,49 -52 and more rarely, in the homozygous form in individuals with hearing loss. 39,51,53 No changes have been reported in the other allele among the M34T carriers in the control groups. Thus, the evidence appears to support the hypothesis that M34T is a recessive allele, although the lack of compound heterozygotes in the control groups may be due to their smaller sample sizes.…”

Section: M34t Allele and Hearing Lossmentioning

confidence: 93%

GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: A HuGE review

Kenneson

Braun

Boyle

2002

Genetics in Medicine

358

323

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Despite the enormous heterogeneity of genetic hearing loss, variants in one locus, Gap Junction Beta 2 or GJB2 (connexin 26), account for up to 50% of cases of nonsyndromic sensorineural hearing loss in some populations. This article reviews genetic epidemiology studies of the alleles of GJB2, prevalence rates, genotype-phenotype relations, contribution to the incidence of hearing loss, and other issues related to the clinical validity of genetic testing for GJB2. This review focuses primarily on three alleles: 167⌬T, 35⌬G, and 235⌬C. These alleles are recessive for nonsyndromic prelingual sensorineural hearing loss, and the evidence suggests complete penetrance but variable expressivity. GENEThe Gap Junction Beta 2 or GJB2 gene (GenBank M86849, OMIM: *121011) resides at the chromosomal location 13q11 and encodes for the protein connexin 26, a beta class gap junction protein expressed in the cochlea and in the epidermis. 3 Connexin 26 hexamers form channels between cells that, when open, allow cell-to-cell diffusion of small molecules. This function is necessary for recycling potassium in the cochlea that plays a critical role in sensorineural hearing function. 4 The GJB2 gene is small, with the entire coding region of 680 base pairs falling within exon 2. GENE VARIANTSAided by the relatively small size of the GJB2 gene, the flourish of activity on the genetics of hearing loss has resulted in rapid identification of GJB2 variants. Missense, nonsense, frameshift, insertion, and deletion variants have all been reported. To identify published genetic epidemiology studies related to GJB2, we searched the MEDLINE database using the keywords GJB2, connexin 26, and hearing loss to identify relevant studies. References in related studies were also reviewed.A list of GJB2 variants is presented in Table 1. Some variants are benign polymorphisms, with a high prevalence rate in various populations. For example, the V27I, E114G, and I203T variants were found on 54%, 55%, and 94% of Japanese chromosomes, respectively. 5,6 The 167⌬T, 35⌬G (also known as 30⌬G), 235⌬C, and R143W alleles are the most common hearing loss-associated GJB2 alleles in the Ashkenazi Jewish, Caucasian, Japanese, and Ghanian populations, respectively. The best-characterized population is Caucasian of northern European descent. Table 2 presents the heterozygote carrier frequencies of the first three alleles either in the general population (hearing status unknown) or in control groups (without hearing loss). Ascertainment details were generally lacking and are listed in Table 2 as described in the publication. Likewise, descriptive information, including sex and age, were generally not provided. Despite these limitations, the studies consistently reported a prevalence of the 35⌬G allele in the range of 1% to 3%. In fact, one population-based study, which genotyped 560 randomly selected neonatal bloodspots in the Midwestern United States, detected a 35⌬G heterozygosity rate of 2.5% in this predominantly Caucasian population. 7 In addition to Caucasians, ...

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Audiologic Phenotype and Progression in GJB2 (Connexin 26) Hearing Loss

Kenna¹,

Feldman²,

Neault³

et al. 2010

Arch Otolaryngol Head Neck Surg

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Objectives To document the audiologic phenotype of children with biallelic GJB2 (connexin 26) mutations, and to correlate it with the genotype. Design Prospective, observational study. Setting Tertiary care children’s hospital. Patients Infants and children with sensorineural hearing loss (SNHL). Intervention Sequencing of the GJB2 (connexin 26) gene. Main Outcome Measures Degree and progression of SNHL. Results From December 1, 1998, through November 30, 2006, 126 children with biallelic GJB2 mutations were identified. Of the 30 different mutations identified, 13 (43%) were truncating and 17 (57%) were nontruncating; 62 patients had 2 truncating, 30 had 1 truncating and 1 nontruncating, and 17 had 2 nontruncating mutations. Eighty-four patients (67%) initially had measurable hearing in the mild to severe range in at least 1 of 4 frequencies (500, 1000, 2000, or 4000 Hz). Of these 84 patients with residual hearing, 47 (56%) had some degree of progressive hearing loss. Patients with 2 truncating mutations had significantly worse hearing compared with all other groups. Patients who had 1 or 2 copies of either an M34T or a V37I allele had the mildest hearing loss. Conclusions Hearing loss owing to GJB2 mutations ranges from mild to profound and is usually congenital. More than 50% of patients will experience some hearing loss progression, generally gradually but occasionally precipitously. Hearing loss severity may be influenced by genetic factors, such as the degree of preserved protein function in nontruncating mutations, whereas hearing loss progression may be dependent on factors other than the connexin 26 protein. Genetic counseling for patients with GJB2 mutations should include the variable audiologic phenotype and the possibility of progression.

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Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss

Cited by 77 publications

References 25 publications

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

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

GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: A HuGE review

Audiologic Phenotype and Progression in GJB2 (Connexin 26) Hearing Loss

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