GJB2 and GJB6 genes and the A1555G mitochondrial mutation are only minor causes of nonsyndromic hearing loss in the Qatari population

Alkowari, Moza Khalifa; Girotto, Giorgia; Abdulhadi, Khalid; Dipresa, Savina; Siam, R.; Najjar, N.M. Al; Badii, Ramin; Gasparini, Paolo

doi:10.3109/14992027.2011.625983

Cited by 25 publications

(17 citation statements)

References 18 publications

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“…As previously described [7], there is no major gene associated with HHL in the Qatari population. In this report, using a combined approach of linkage studies with massively parallel sequencing, we analyzed a second degree consanguineous family not linked to any known HHL gene.…”

Section: Discussionmentioning

confidence: 64%

“…Previous molecular studies showed that the family under investigation was negative for the presence of mutations in the most common worldwide NSHHL genes ( GJB2 , GJB6 and A1555G mitochondrial mutation) [7], suggesting that this family should harbor a mutation in another HHL gene or in a new gene involved in the HL phenotype. Taking into account the power of linkage studies coupled with massively parallel sequencing technologies, we decided to apply these approaches to identify the causative mutation underlying NSHHL in this Qatari family.…”

Section: Resultsmentioning

confidence: 95%

“…As regards the Qatari population, a recent study using high-density SNP arrays revealed three clusters consistent with Arabian origin, an eastern or Persian origin and individuals with African admixture [6]. A previous report on HHL in the Qatari population demonstrated a minor role for the GJB2 gene but no role for GJB6 or the A1555G mutation, strongly suggesting the presence of additional causative mutations [7]. Here, we report the identification of a gene, never described before as involved in HHL, by linkage study followed by exome sequencing carried out in a NSHHL Qatari family with second degree consanguinity.…”

Section: Introductionmentioning

confidence: 98%

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Linkage Study and Exome Sequencing Identify a BDP1 Mutation Associated with Hereditary Hearing Loss

et al. 2013

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Nonsyndromic Hereditary Hearing Loss is a common disorder accounting for at least 60% of prelingual deafness. GJB2 gene mutations, GJB6 deletion, and the A1555G mitochondrial mutation play a major role worldwide in causing deafness, but there is a high degree of genetic heterogeneity and many genes involved in deafness have not yet been identified. Therefore, there remains a need to search for new causative mutations. In this study, a combined strategy using both linkage analysis and sequencing identified a new mutation causing hearing loss. Linkage analysis identified a region of 40 Mb on chromosome 5q13 (LOD score 3.8) for which exome sequencing data revealed a mutation (c.7873 T>G leading to p.*2625Gluext*11) in the BDP1 gene (B double prime 1, subunit of RNA polymerase III transcription initiation factor IIIB) in patients from a consanguineous Qatari family of second degree, showing bilateral, post-lingual, sensorineural moderate to severe hearing impairment. The mutation disrupts the termination codon of the transcript resulting in an elongation of 11 residues of the BDP1 protein. This elongation does not contain any known motif and is not conserved across species. Immunohistochemistry studies carried out in the mouse inner ear showed Bdp1 expression within the endothelial cells in the stria vascularis, as well as in mesenchyme-derived cells surrounding the cochlear duct. The identification of the BDP1 mutation increases our knowledge of the molecular bases of Nonsyndromic Hereditary Hearing Loss and provides new opportunities for the diagnosis and treatment of this disease in the Qatari population.

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Section: Discussionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

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Linkage Study and Exome Sequencing Identify a BDP1 Mutation Associated with Hereditary Hearing Loss

et al. 2013

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“…The Role of Connexin Genes Recently, the first mutational screening of gene GJB2 , GJB6 (a deletion) and mitochondrial DNA (an A1555G transition in the 12S rRNA gene) has been carried out in a large cohort of 120 patients from Qatar [15] . The results of the largest collection of Qatari cases described so far demonstrate only a minor role for the GJB2 gene.…”

Section: The Genetics Of Hhl In Qatarmentioning

confidence: 99%

“…We took all SNPs of the genes discovered in previous studies of hearing loss in Qatari samples [15,25,26] and we estimated the haplotype diversity in these genes with respect to other reference populations. The haplotypes were phased using an expectation-maximization procedure implemented in PLINK.…”

Section: The Role Of Other Genesmentioning

confidence: 99%

Consanguinity and Hereditary Hearing Loss in Qatar

et al. 2014

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Qatar is a sovereign state located on the Eastern coast of the Arabian Peninsula in the Persian Gulf. Its native population consists of 3 major subgroups: people of Arabian origin or Bedouins, those from an Eastern or Persian ancestry and individuals with African admixture. Historically, all types of consanguineous marriages have been and still are common in the Qatari population, particularly among first and double-first cousins. Thus, there is a higher risk for most inherited diseases including hereditary hearing loss (HHL). In particular, a hearing loss prevalence of 5.2% has been reported in Qatar, with parental consanguinity being more common among affected individuals as compared with unaffected ones. Our recent molecular results confirm a high homogeneity and level of inbreeding in Qatari HHL patients. Among all HHL genes, GJB2, the major player worldwide, accounts for a minor proportion of cases and at least 3 additional genes have been found to be mutated in Qatari patients. Interestingly, one gene, BDP1, has been described to cause HHL only in this country. These results point towards an unexpected level of genetic heterogeneity despite the high level of inbreeding. This review provides an up-to-date picture of HHL in Qatar and of the impact of consanguinity on this disease.

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GJB2-associated hearing loss: Systematic review of worldwide prevalence, genotype, and auditory phenotype

2013

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GJB2 mutations are highly prevalent around the world. The multiple predominant mutations present in different populations attest to the importance of this gene for normal cochlear function and suggests an evolutionary heterozygote advantage. The unusually high carrier rate for truncating mutations among hearing-impaired individuals is consistent with either the presence of complementary mutations or a carrier phenotype. The significant rate of asymmetry and progression highlights the importance of diagnostic workup and close follow-up for this highly variable condition.

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GJB2 and GJB6 genes and the A1555G mitochondrial mutation are only minor causes of nonsyndromic hearing loss in the Qatari population

Cited by 25 publications

References 18 publications

Linkage Study and Exome Sequencing Identify a BDP1 Mutation Associated with Hereditary Hearing Loss

Linkage Study and Exome Sequencing Identify a BDP1 Mutation Associated with Hereditary Hearing Loss

Consanguinity and Hereditary Hearing Loss in Qatar

GJB2-associated hearing loss: Systematic review of worldwide prevalence, genotype, and auditory phenotype

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