Novel pathogenic variants underlie SLC26A4 -related hearing loss in a multiethnic cohort

Cengiz, Filiz Başak; Yilmazer, Rasim; Olgun, Levent; Sennaroḡlu, Levent; Kirazlı, Tayfun; Alper, Hüdaver; Olgun, Yüksel; İncesulu, Armağan; Atik, Tahir; Huesca-Hernández, Fabiola; Domínguez-Aburto, Juan; González-Rosado, Garly; Hernández-Zamora, Edgar; Arenas-Sordo, María de la Luz; Menéndez, Ibis; Orhan, Kadir Serkan; Avcı, Hakan; Mahdieh, Nejat; Bonyadi, Mortaza; Foster, Joseph; Duman, Duygu; Özkınay, Ferda; Blanton, Susan H.; Bademci, Güney; Tekin, Mustafa

doi:10.1016/j.ijporl.2017.08.006

Cited by 14 publications

(12 citation statements)

References 30 publications

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“…48 In addition, mutations in GJB2 and SLC26A4 genes were associated with NSHL. 49,50 To understand the contributions of nuclear gene mutations to hearing loss, we screened the mutations in GJB2 and SLC26A4 genes, but no variants were identified.…”

Section: Discussionmentioning

confidence: 99%

Maternally transmitted nonsyndromic hearing impairment may be associated with mitochondrial tRNA^Ala 5601C>T and tRNA^Leu(CUN) 12311T>C mutations

Ding

2022

Clinical Laboratory Analysis

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Background: Sequence alternations in mitochondrial genomes, especially in genes encoding mitochondrial tRNA (mt-tRNA), were the important contributors to nonsyndromic hearing loss (NSHL); however, the molecular mechanisms remained largely undetermined. Methods:A maternally transmitted Chinese pedigree with NSHL underwent clinical, genetic, and biochemical assessment. PCR and direct sequence analyses were performed to detect mitochondrial DNA (mtDNA), GJB2, and SLC26A4 gene mutations from matrilineal relatives of this family. Mitochondrial functions including mitochondrial membrane potential (MMP), ATP, and ROS were evaluated in polymononuclear leukocytes (PMNs) derived from three deaf patients and three controls from this pedigree.Results: Four of nine matrilineal relatives developed hearing loss at the variable age of onset. Two putative pathogenic mutations, m.5601C>T in tRNA Ala and m.12311T>C in tRNA Leu(CUN) , were identified via PCR-Sanger sequencing, as well as 34 variants that belonged to mtDNA haplogroup G2b2. Intriguingly, m.5601C>T mutation resided at very conserved nucleotide in the TψC loop of tRNA Ala (position 59), while the T-to-C substitution at position 12311 located at position 48 in the variable stem of tRNA Leu(CUN) and was believed to alter the aminoacylation and the steady-state level of tRNA. Biochemical analysis revealed the impairment of mitochondrial functions including the significant reductions of ATP and MMP, whereas markedly increased ROS levels were found in PMNs derived from NSHL patients with m.5601C>T and m.12311T>C mutations. However, we did not detect any mutations in GJB2 and SLC26A4 genes. Conclusion:Our data indicated that mt-tRNA Ala m.5601C>T and tRNA Leu(CUN) 12311T>C mutations were associated with NSHL.

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Section: Discussionmentioning

confidence: 99%

Maternally transmitted nonsyndromic hearing impairment may be associated with mitochondrial tRNA^Ala 5601C>T and tRNA^Leu(CUN) 12311T>C mutations

Ding

2022

Clinical Laboratory Analysis

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“…This mutation leads to the formation of a stop codon at amino acid position 57 (p.Ser57Ter) at the NH 2 -terminus of the pendrin molecule, and the protein is predicted to lack most of the important domains [ 67 ]. The c.170C>A (p.Ser57Ter) mutation was previously found in several deaf patients from India, China, Pakistan, Mexico, and Turkey [ 6 , 28 , 66 , 67 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

Different Rates of the SLC26A4-Related Hearing Loss in Two Indigenous Peoples of Southern Siberia (Russia)

et al. 2021

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Hereditary hearing loss (HL) is known to be highly locus/allelic heterogeneous, and the prevalence of different HL forms significantly varies among populations worldwide. Investigation of region-specific landscapes of hereditary HL is important for local healthcare and medical genetic services. Mutations in the SLC26A4 gene leading to nonsyndromic recessive deafness (DFNB4) and Pendred syndrome are common genetic causes of hereditary HL, at least in some Asian populations. We present for the first time the results of a thorough analysis of the SLC26A4 gene by Sanger sequencing in the large cohorts of patients with HL of unknown etiology belonging to two neighboring indigenous Turkic-speaking Siberian peoples (Tuvinians and Altaians). A definite genetic diagnosis based on the presence of biallelic SLC26A4 mutations was established for 28.2% (62/220) of all enrolled Tuvinian patients vs. 4.3% (4/93) of Altaian patients. The rate of the SLC26A4-related HL in Tuvinian patients appeared to be one of the highest among populations worldwide. The SLC26A4 mutational spectrum was characterized by the presence of Asian-specific mutations c.919-2A>G and c.2027T>A (p.Leu676Gln), predominantly found in Tuvinian patients, and c.2168A>G (p.His723Arg), which was only detected in Altaian patients. In addition, a novel pathogenic variant c.1545T>G (p.Phe515Leu) was found with high frequency in Tuvinian patients. Overall, based on the findings of this study and our previous research, we were able to uncover the genetic causes of HL in 50.5% of Tuvinian patients and 34.5% of Altaian patients.

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“…For example, at the DFNA1 locus (OMIM #124900) is the DIAPH1 gene (OMIM *602121) on 5q31. 1) [19][20][21][22][23][24][25] .…”

Section: Syndromic Genetic Causes Of Hearing Loss Includementioning

confidence: 99%

Congenital hearing loss: a literature review of the genetic etiology in a Mexican population

Torre-González¹,

Villanueva-García²,

García-Delgado³

et al. 2022

BMHIM

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Hearing loss is the most frequent sensory disorder, with an incidence of 1:1500 live newborns. In more than 50% of patients, it is associated with a genetic cause, while in up to 30% of cases, it is related to syndromic entities. We performed a literature review of studies on congenital hearing loss of genetic origin in the Mexican population. We identified eight reports that showed that the pathogenic variants most frequently associated with hearing loss are related to the GJB2 gene, although in a low percentage (3%). Other mutations were identified in the GJB6, SLC26A4, or CHD23 genes. On this basis, a possible diagnostic strategy in Mexican patients with hearing loss is to consider an initial screening of these three genes. If these genes were negative for pathogenic variants, the following steps would be to consider second-generation sequencing analysis focused on panels of genes associated with hearing loss, isolated or syndromic, and if necessary, to perform exome or whole-genome analysis. Establishing an etiologic cause is critical in clinically evaluating patients with congenital hearing loss and their families. It can help determine rehabilitation strategies, such as hearing aids or cochlear implants and provide information on disease progression and genetic counseling in this population.

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Novel pathogenic variants underlie SLC26A4 -related hearing loss in a multiethnic cohort

Cited by 14 publications

References 30 publications

Maternally transmitted nonsyndromic hearing impairment may be associated with mitochondrial tRNA^Ala 5601C>T and tRNA^Leu(CUN) 12311T>C mutations

Maternally transmitted nonsyndromic hearing impairment may be associated with mitochondrial tRNA^Ala 5601C>T and tRNA^Leu(CUN) 12311T>C mutations

Different Rates of the SLC26A4-Related Hearing Loss in Two Indigenous Peoples of Southern Siberia (Russia)

Congenital hearing loss: a literature review of the genetic etiology in a Mexican population

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Novel pathogenic variants underlie SLC26A4 -related hearing loss in a multiethnic cohort

Cited by 14 publications

References 30 publications

Maternally transmitted nonsyndromic hearing impairment may be associated with mitochondrial tRNAAla 5601C>T and tRNALeu(CUN) 12311T>C mutations

Maternally transmitted nonsyndromic hearing impairment may be associated with mitochondrial tRNAAla 5601C>T and tRNALeu(CUN) 12311T>C mutations

Different Rates of the SLC26A4-Related Hearing Loss in Two Indigenous Peoples of Southern Siberia (Russia)

Congenital hearing loss: a literature review of the genetic etiology in a Mexican population

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Maternally transmitted nonsyndromic hearing impairment may be associated with mitochondrial tRNA^Ala 5601C>T and tRNA^Leu(CUN) 12311T>C mutations

Maternally transmitted nonsyndromic hearing impairment may be associated with mitochondrial tRNA^Ala 5601C>T and tRNA^Leu(CUN) 12311T>C mutations