Salicylate restores transport function and anion exchanger activity of missense pendrin mutations

Ishihara, Kenji; Okuyama, Shuhei; Kumano, Shun; Iida, Kei; Hamana, Hiroshi; Murakoshi, Michio; Kobayashi, Toshimitsu; Usami, Shin‐ichi; Ikeda, Katsuhisa; Haga, Yoichi; Tsumoto, Kouhei; Nakamura, Hiroyuki; Hirasawa, Noriyasu; Wada, Hiroshi

doi:10.1016/j.heares.2010.08.015

Cited by 43 publications

(52 citation statements)

References 37 publications

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“…Recently, Ishihara et al [2010] reported that salicylate restored the transport function and anion exchanger activity of missense pendrin mutants. In that study, among 8 pendrin mutants (p.P123S, p.M147V, p.A372V, p.N392Y, p.S657N, p.S666F, p.T721M and p.H723R) that remained in the cytoplasm, 4 (p.P123S, p.M147V, p.S657S and p.H723R) were transported from the cytoplasm to the plasma membrane with 10 m M salicylate, leading to restoration of anion exchange activity [Ishihara et al, 2010]. They proposed that the difference in responses to salicylate among the 8 mutants might be due to different processing or localization in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…In these studies, PS with iodide organification defect was shown to be strongly associated with 2 mutant alleles of SLC26A4 (M2), while NSEVA was frequently correlated with only 1 (M1) or no mutation (M0). Some researchers have also reported that the degree of hearing loss was correlated with the number of mutant alleles of SLC26A4 in a Caucasian population [Albert et al, 2006;Ishihara et al, 2010]. Furthermore, a correlation between the degree of residual hearing and the type of SLC26A4 variant within the M2 EVA group was reported recently in a Korean population with a higher proportion of M2 EVA subjects [Lee et al, 2013].…”

Section: Introductionmentioning

confidence: 89%

“…Recently, several studies have reported that the abnormal transport function and abolished anion exchange activity of some missense pendrin mutants, such as p.H723R, could be restored substantially simply by inducing plasma membrane targeting of the mutant using a chemical chaperone, low temperature incubation or drugs such as salicylate [Ishihara et al, 2010;Yoon et al, 2008]. Missense pendrin mutants produce abnormal proteins which are retained in the ER as a result of misfolding, which is the main pathogenic mechanism of PS [Rotman-Pikielny et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Taylor et al successively measured the activity of mutated pendrin using radiolabeled iodide efflux assays in human cells transfected with WT and mutated pendrin [82]. The use of human cells instead of a non-mammalian system for chloride uptake [32] and iodide efflux [83][84][85] …”

Section: Functional Testsmentioning

confidence: 99%

“…They could, therefore, be classified as hypofunctional allelic variants [89]. Moreover, the function of C565Y, L597S, and R776C is controversial, as these allelic variants were classified as benign polymorphisms by other Authors [83,85,86] (Fig. 3).…”

Section: Intracellular Localizationmentioning

confidence: 99%

Molecular and Functional Characterization of Human Pendrin and its Allelic Variants

Dossena

Nofziger

Tamma

et al. 2011

Cell Physiol Biochem

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Pendrin (SLC26A4, PDS) is an electroneutral anion exchanger transporting I ^-, Cl ^-, HCO₃^-, OH ^-, SCN ^- and formate. In the thyroid, pendrin is expressed at the apical membrane of the follicular epithelium and may be involved in mediating apical iodide efflux into the follicle; in the inner ear, it plays a crucial role in the conditioning of the pH and ion composition of the endolymph; in the kidney, it may exert a role in pH homeostasis and regulation of blood pressure. Mutations of the pendrin gene can lead to syndromic and non-syndromic hearing loss with EVA (enlarged vestibular aqueduct). Functional tests of mutated pendrin allelic variants found in patients with Pendred syndrome or non-syndromic EVA (ns-EVA) revealed that the pathological phenotype is due to the reduction or loss of function of the ion transport activity. The diagnosis of Pendred syndrome and ns-EVA can be difficult because of the presence of phenocopies of Pendred syndrome and benign polymorphisms occurring in the general population. As a consequence, defining whether or not an allelic variant is pathogenic is crucial. Recently, we found that the two parameters used so far to assess the pathogenic potential of a mutation, i.e. low incidence in the control population, and substitution of evolutionary conserved amino acids, are not always reliable for predicting the functionality of pendrin allelic variants; actually, we identified mutations occurring with the same frequency in the cohort of hearing impaired patients and in the control group of normal hearing individuals. Moreover, we identified functional polymorphisms affecting highly conserved amino acids. As a general rule however, we observed a complete loss of function for all truncations and amino acid substitutions involving a proline. In this view, clinical and radiological studies should be combined with genetic and molecular studies for a definitive diagnosis. In performing genetic studies, the possibility that the mutation could affect regions other than the pendrin coding region, such as its promoter region and/or the coding regions of functionally related genes (FOXI1, KCNJ10), should be taken into account. The presence of benign polymorphisms in the population suggests that genetic studies should be corroborated by functional studies; in this context, the existence of hypo-functional variants and possible differences between the I ^-/Cl ^- and Cl ^-/HCO₃^- exchange activities should be carefully evaluated.

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Congenital Deafness and Recent Advances Towards Restoring Hearing Loss

Renauld

Basch

2021

Current Protocols

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Congenital hearing loss is the most common birth defect, estimated to affect 2‐3 in every 1000 births. Currently there is no cure for hearing loss. Treatment options are limited to hearing aids for mild and moderate cases, and cochlear implants for severe and profound hearing loss. Here we provide a literature overview of the environmental and genetic causes of congenital hearing loss, common animal models and methods used for hearing research, as well as recent advances towards developing therapies to treat congenital deafness. © 2021 The Authors.

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Salicylate restores transport function and anion exchanger activity of missense pendrin mutations

Cited by 43 publications

References 37 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

Molecular and Functional Characterization of Human Pendrin and its Allelic Variants

Congenital Deafness and Recent Advances Towards Restoring Hearing Loss

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