Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss

Dai, Pu; Stewart, Andrew K.; Chebib, Fouad T.; Hsu, Ann; Rozenfeld, Julia; Huang, Deliang; Kang, Dongyang; Lip, Va; Fang, Hong; Shao, Hong; Liu, Xin; Yu, Fei; Yuan, Huijun; Kenna, Margaret A.; Miller, David T.; Shen, Yiping; Wei, Yang; Zelikovic, Israel; Platt, Orah S.; Han, Dongyi; Alper, Seth L.; Wu, Bai Lin

doi:10.1152/physiolgenomics.00047.2009

Cited by 60 publications

(63 citation statements)

References 38 publications

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“…It is as yet unclear whether the abolished anion exchange activity of p.V510D is attributable to protein mislocalization, an intrinsic defect in exchange activity or both. Complete loss of anion base exchange activity despite significant plasma membrane trafficking of a mutant pendrin likely indicates an intrinsic defect in exchange activity, as described previously for p.E303Q [Dai et al, 2009] (online suppl. table 1; for all online suppl.…”

Section: Discussionsupporting

confidence: 69%

Identification of Novel Functional Null Allele of SLC26A4 Associated with Enlarged Vestibular Aqueduct and Its Possible Implication

et al. 2014

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Mutations in the SLC26A4 gene, which encodes pendrin, cause congenital hearing loss as a manifestation of Pendred syndrome (PS) with an iodide organification defect or nonsyndromic enlarged vestibular aqueduct (NSEVA, DFNB4). There have been reports of differences between PS and NSEVA, including their auditory phenotypes and molecular genetic bases. For appropriate genetic diagnosis and counseling, it is important to functionally characterize SLC26A4 variants. In this study, we identified and evaluated a novel null mutation of SLC26A4 and report our method of assessing the pathogenic potential of mutations in SLC26A4, one of the most frequent causative genes of deafness in humans. A 3-year-old female with progressive sensorineural hearing loss and her parents were recruited. They underwent clinical, audiological, radiological and genetic evaluations, which revealed that the female patient had an enlarged vestibular aqueduct and an incomplete partition type II anomaly in the cochlea bilaterally. Sanger sequencing of the SLC26A4 gene was also performed. For a confirmatory genetic diagnosis, we first characterized the anion/base exchange ability of mutant pendrin products in HEK 293 cells and, if necessary, evaluated whether the mutant pendrin traffics to the plasma membrane in COS-7 cells. We also expressed a null function mutant, p.H723R, and a previously documented polymorphism, p.P542R, as controls. The pure tone average was 66 dB HL in the right ear and 75 dB HL in the left ear. Sequencing of SLC26A4 revealed a known pathogenic mutation (p.H723R) and a novel missense variant (p.V510D) as a compound heterozygote. When we expressed the p.V510D mutant pendrin in mammalian cells, the rate constants for Cl^-/HCO₃^- exchange were 10.96 ± 4.79% compared with those of wild-type pendrin. This figure was comparable to that of p.H723R, indicating p.V510D to be another pathogenic mutation with a null function. The p.V510D pendrin product was shown to be entrapped in the endoplasmic reticulum (ER) at 24-30 h after transfection, and not trafficked to the plasma membrane in COS-7 cells, suggesting retention in the ER and abnormal trafficking as the pathogenic mechanism. This was similar to p.H723R, which is a null function founder mutant in this population but is a candidate variant for future drug therapy to rescue the abnormal cell trafficking. Impaired cellular trafficking due to ER retention and abolished exchange activity of the newly detected p.V510D indicates the pathogenic potential of this variant. These missense variants may be good candidate variants for drug therapy if the intrinsic exchange activity is not damaged by the change.

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Section: Discussionsupporting

confidence: 69%

Identification of Novel Functional Null Allele of SLC26A4 Associated with Enlarged Vestibular Aqueduct and Its Possible Implication

et al. 2014

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“…Although prescreening in these 137 patients was negative and therefore WES was performed, it is known that patients with a specific phenotype associated with mutations in one or a few genes (eg, Pendred syndrome) are quite often solved by targeted testing. 19 To evaluate the utility of prescreening in individuals with HI, we made an overview of all in-house gene analysis requests for HI in 2013-2014 and the diagnostic yield (Supplementary Table S5). The vast majority of these tests were performed in patients of Dutch origin.…”

Section: Prescreening Of Single Genesmentioning

confidence: 99%

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

et al. 2016

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Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

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“…The c.35delG, c.167delT, c.235delC, and c.427C > T (p.R143W) in the GJB2 gene are the most prevalent mutations among Caucasians, Ashkenazi Jews, Asian, and African populations, respectively , which support the ethnic differences in the genetic pathogenesis of deafness. A characteristic SLC26A4 mutation spectrum is identifiable in highly prevalent mutations, such as c.IVS7-2A > G and p.H723R in East Asian subjects, but is rare in European lineages (Dai et al, 2009). Exposure to aminoglycoside antibiotics can cause hypersensitivity and ototoxicity in patients carrying the 1555A > G or 1494C > T mutation in the mtDNA gene, leading to severe or profound sensorineural hearing loss (SNHL).…”

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confidence: 99%

Prevalence of Mutations in GJB2, SLC26A4, and mtDNA in Children with Severe or Profound Sensorineural Hearing Loss in Southwestern China

Zhou

Lai

et al. 2015

Genetic Testing and Molecular Biomarkers

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Aim: To study the distribution characteristics of common mutations in the GJB2, SLC26A4, and mtDNA genes in children with severe or profound sensorineural hearing loss (SNHL) in southwestern China. Materials and Methods: A total of 1,164 individuals were recruited to screen for the common GJB2, SLC26A4, and mtDNA mutations by microarrays. Subsequencing for the coding region of the GJB2 gene in the samples without the GJB2 hotspot mutations as well as subsequencing for the exon 1 of the TRMU gene in those samples with the mtDNA hotspot mutations was performed by Sanger sequencing. All mutations were analyzed in association with medical imaging. Results: In this study, 28.43% of all subjects carried mutations. The mutation frequencies in the GJB2, SLC26A4, and mtDNA genes were 17.27%, 7.04%, and 4.12%, respectively. No TRMU mutation was found in the study. The frequency of the mtDNA mutations in the multiethnic minorities was six times that in the Han (11.23% vs. 1.91%; p approaches 0.000) and in the urban group was one-third of that in the suburban group(1.49% vs. 4.47%; p = 0.047). The frequency of the GJB2 mutations in urban and suburban groups was 23.38% and 15.99%, respectively ( p = 0.012). The enlarged vestibular aqueduct (EVA) was the most common inner ear malformation and *79.10% of EVA cases were associated with the SLC26A4 mutations. Conclusions: More than one-fourth of children with severe or profound SNHL carried the common deafness mutations. The proportions of ethnic minorities and urban subjects could impact the frequency of the GJB2 and mtDNA mutations. The SLC26A4 hotspot mutations are prevalent and correlate strongly with EVA.

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Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss

Cited by 60 publications

References 38 publications

Identification of Novel Functional Null Allele of <b><i>SLC26A4</i></b> Associated with Enlarged Vestibular Aqueduct and Its Possible Implication

Identification of Novel Functional Null Allele of <b><i>SLC26A4</i></b> Associated with Enlarged Vestibular Aqueduct and Its Possible Implication

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

Prevalence of Mutations in GJB2, SLC26A4, and mtDNA in Children with Severe or Profound Sensorineural Hearing Loss in Southwestern China

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