Screening of the <i>DFNB3</i> Locus: Identification of Three Novel Mutations of <i>MYO15A</i> Associated with Hearing Loss and Further Suggestion for Two Distinctive Genes on This Locus

Belguith, Hanen; Aifa-Hmani, Mounira; Dhouib, H.; Said, Mariem Ben; Mosrati, Mohamed Ali; Lahmar, Imed; Moalla, J; Charfeddine, Ilhem; Driss, Nabil; Arab, Saïda Ben; Ghorbel, Abdelmonem; Ayadi, Hammadi; Masmoudi, Saber

doi:10.1089/gtmb.2008.0077

Cited by 36 publications

(25 citation statements)

References 22 publications

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“…Five of the 11 genes we found mutated in this study have been reported in other families from Turkey, supporting our findings for their relatively high frequency in the Turkish population (Tekin et al, 2003(Tekin et al, , 2005Kalay et al, 2005Kalay et al, , 2007Wattenhofer et al, 2005;Ahmed et al, 2008). In addition, mutations in MYO15A, TMC1, and OTOF were reported with 5%, 3.4%, and 2.3% frequencies, respectively, in the deaf populations from Pakistan (Kitajiri et al, 2007;Nal et al, 2007;Choi et al, 2009), and mutations in MYO15A and TMC1 were found in 7.8% and 3.9%, respectively, of families without GJB2 mutations from Tunisia (Tlili et al, 2008;Belguith et al, 2009). Founder effects, heterozygote advantage, and assortative mating have all been proposed to explain the relatively high frequency of GJB2 (Gasparini et al, 2000;Nance et al, 2000;Van Laer et al, 2001;Meyer et al, 2002).…”

Section: Discussionsupporting

confidence: 91%

Screening of 38 Genes Identifies Mutations in 62% of Families with Nonsyndromic Deafness in Turkey

Duman

Sırmacı

Cengiz

et al. 2011

Genetic Testing and Molecular Biomarkers

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More than 60% of prelingual deafness is genetic in origin, and of these up to 95% are monogenic autosomal recessive traits. Causal mutations have been identified in 1 of 38 different genes in a subset of patients with nonsyndromic autosomal recessive deafness. In this study, we screened 49 unrelated Turkish families with at least three affected children born to consanguineous parents. Probands from all families were negative for mutations in the GJB2 gene, two large deletions in the GJB6 gene, and the 1555A>G substitution in the mitochondrial DNA MTRNR1 gene. Each family was subsequently screened via autozygosity mapping with genomewide single-nucleotide polymorphism arrays. If the phenotype cosegregated with a haplotype flanking one of the 38 genes, mutation analysis of the gene was performed. We identified 22 different autozygous mutations in 11 genes, other than GJB2, in 26 of 49 families, which overall explains deafness in 62% of families. Relative frequencies of genes following GJB2 were MYO15A (9.9%), TMIE (6.6%), TMC1 (6.6%), OTOF (5.0%), CDH23 (3.3%), MYO7A (3.3%), SLC26A4 (1.7%), PCDH15 (1.7%), LRTOMT (1.7%), SERPINB6 (1.7%), and TMPRSS3 (1.7%). Nineteen of 22 mutations are reported for the first time in this study. Unknown rare genes for deafness appear to be present in the remaining 23 families.

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Section: Discussionsupporting

confidence: 91%

Screening of 38 Genes Identifies Mutations in 62% of Families with Nonsyndromic Deafness in Turkey

Duman

Sırmacı

Cengiz

et al. 2011

Genetic Testing and Molecular Biomarkers

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“…We may have missed some mutations even in the exons because our screening method was not 100% sensitive. An alternative explanation is the presence of yet another deafness gene at the DFNB3 locus, which has been previously suggested (Nal et al, 2007;Belguith et al, 2009;Shahin et al, 2010).…”

Section: Discussionmentioning

confidence: 96%

Recurrent and Private MYO15A Mutations Are Associated with Deafness in the Turkish Population

Cengiz

Duman

Sırmacı

et al. 2010

Genetic Testing and Molecular Biomarkers

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The identities and frequencies of MYO15A mutations associated with hearing loss in different populations remained largely unknown. We screened the MYO15A gene for mutations in 104 unrelated multiplex and consanguineous Turkish families with autosomal recessive nonsyndromic sensorineural hearing loss using autozygosity mapping. The screening of MYO15A in 10 families mapped to the DFNB3 locus revealed five previously unreported mutations: p.Y289X (1 family), p.V1400M (1 family), p.S1481P (1 family), p.R1937TfsX10 (3 families), and p.S3335AfsX121 (2 families). Recurrent mutations were associated with conserved haplotypes suggesting the presence of founder effects. Severe to profound sensorineural hearing loss was observed in all subjects with homozygous mutations except for two members of a family who were homozygous for the p.Y289X mutation in the N-terminal extension domain and had considerable residual hearing. We estimate the prevalence of homozygous MYO15A mutations in autosomal recessive nonsyndromic deafness in Turkey as 0.062 (95% confidence interval is 0.020-0.105).

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“…31. PDZD7 was predicted to encode a protein smaller than harmonin or whirlin with only 2 PDZ domains.…”

Section: Pdzd7 Encodes a Ciliary Protein With Homology To The Ush1c Amentioning

confidence: 99%

“…Moreover, presence of p.L3160F MYO15A in a healthy control has been reported, and at least one additional deafness gene is predicted for the DFNB3 locus (31). Hence, p.L3160F MYO15A may be a benign variant, and a heterozygous mutation of an as yet unknown gene with cochlear and retinal function probably contributes to the Usher phenotype of U329-1 (digenic inheritance).…”

Section: Figurementioning

confidence: 99%

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Ebermann¹,

Phillips²,

Liebau³

et al. 2010

J. Clin. Invest.

204

167

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Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain-containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein-coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.

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Screening of the DFNB3 Locus: Identification of Three Novel Mutations of MYO15A Associated with Hearing Loss and Further Suggestion for Two Distinctive Genes on This Locus

Cited by 36 publications

References 22 publications

Screening of 38 Genes Identifies Mutations in 62% of Families with Nonsyndromic Deafness in Turkey

Screening of 38 Genes Identifies Mutations in 62% of Families with Nonsyndromic Deafness in Turkey

Recurrent and Private MYO15A Mutations Are Associated with Deafness in the Turkish Population

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

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