GJB2 and hearing impairment: promoter defects do not explain the excess of monoallelic mutations

Pollak, Agnieszka; Mueller-Malesińska, Małgorzata; Skórka, Agata; Kostrzewa, Grażyna; Ołdak, Monika; Korniszewski, L; Skarżyńśki, Henryk; Płoski, Rafał

doi:10.1136/jmg.2008.059873

Cited by 16 publications

(12 citation statements)

References 7 publications

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“…Only cases with bilateral HL, starting at an age between 5 and 40 years, and with available archived DNA sample, were included in the study. Patients were excluded if they had an established cause of hearing impairment, had syndromic HL of known genetic origin, or had two mutations in the connexin genes GJB2 and GJB6 (homozygosity or compound heterozygosity status) [27], [28]. In total, 1482 archived blood DNA samples were made available for the m.3243A>G mutation search.…”

Section: Methodsmentioning

confidence: 99%

Postlingual Hearing Loss as a Mitochondrial 3243A>G Mutation Phenotype

et al. 2012

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BackgroundThe prevalence of isolated hearing loss (HL) associated with the m.3243A>G mutation is unknown. The aim of this study was to assess the frequency and heteroplasmy level of the m.3243A>G mutation in a large group of Polish patients with postlingual bilateral sensorineural HL of unidentified cause.Methodology/Principal FindingsA molecular search was undertaken in the archival blood DNA of 1482 unrelated patients with isolated HL that had begun at ages between 5 and 40 years. Maternal relatives of the probands were subsequently investigated and all carriers underwent audiological tests. The m.3243A>G mutation was found in 16 of 1482 probands (an incidence of 1.08%) and 18 family members. Of these 34 individuals, hearing impairment was detected in 29 patients and the mean onset of HL was at 26 years. Some 42% of the identified m.3243A>G carriers did not develop multisystem symptomatology over the following 10 years. Mean heteroplasmy level of m.3243A>G was lowest in blood at a level of 14% and highest in urine at 58%. These values were independent of the manifested clinical severity of the disease.ConclusionsA single m.3243A>G carrier can usually be found among each 100 individuals who have postlingual hearing loss of unknown cause. Urine samples are best for detecting the m.3243A>G mutation and diagnosing mitochondrially inherited hearing loss.

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Section: Methodsmentioning

confidence: 99%

Postlingual Hearing Loss as a Mitochondrial 3243A>G Mutation Phenotype

et al. 2012

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“…We directly sequenced amplifi ed PCR fragments of the coding region (exon 2) of the GJB2 gene (Sobe et al, 2000) to identify GJB2 mutations. In heterozygous samples, we also analysed exon 1 as described in Pollak et al, 2008. In heterozygous samples and samples that were negative for GJB2 mutations, we looked for the two hearing-loss related deletions of the GJB6 gene (del GJB6 -D13S1830 and del GJB6 -D13S1854), using the combined detection procedure described by del Castillo et al (2005). The control DNA sample was provided by Dr.…”

Section: Molecular Analysismentioning

confidence: 99%

Screening forGJB2andGJB6gene mutations in patients from Campania region with sensorineural hearing loss

Chinetti

Iossa

Auletta

et al. 2010

International Journal of Audiology

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The aim of this study was to screen 349 patients affected by sensorineural hearing loss (SNHL), mostly from the Campania region (southern Italy), for GJB2 gene mutations and for two deletions of the GJB6 gene (del GJB6 -D13S1830 and del GJB6 -D13S1854). We identified pathogenetic GJB2 mutations in 51 cases (15% of patients). No GJB6 mutation was found. We also examined the audiologic features of the patients for whom we had an etiologic diagnosis, in order to identify correlations between the severity of hearing loss and the type of mutation.

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“…This raises the suggestion that a second mutation in GJB2 was not detected by sequencing (mutation in promoter region, intronic mutation or splicing site mutation) or that the presence of mutations in other genes not tested in this study is causative for hearing loss. This relative high frequency of monoallelic 35delG mutations has indeed been noticed previously [48][49][50]. Referring to promoter defects in GJB2 as a possible explanation for this fact Pollak et al [48] did not reveal sequence alterations in the promoter region of GJB2 whereas Matos et al(2007) detected a basal promoter mutation which can abolish the promoter acitivity of GJB2.…”

Section: Discussionmentioning

confidence: 72%

“…This relative high frequency of monoallelic 35delG mutations has indeed been noticed previously [48][49][50]. Referring to promoter defects in GJB2 as a possible explanation for this fact Pollak et al [48] did not reveal sequence alterations in the promoter region of GJB2 whereas Matos et al(2007) detected a basal promoter mutation which can abolish the promoter acitivity of GJB2. Alongside, standard PCR amplification of exon 2 for sequencing analysis is unable to detect gross deletions or sequence variations in the promoter site or the transcription regulating regions.…”

Section: Discussionmentioning

confidence: 72%