Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/327225
Type: Artigo
Title: Reduction Of Cellular Expression Levels Is A Common Feature Of Functionally Affected Pendrin (slc26a4) Protein Variants
Author: de Moraes
Vanessa C. S.; Bernardinelli
Emanuele; Zocal
Nathalia; Fernandez
Jhonathan A.; Nofziger
Charity; Castilho
Arthur M.; Sartorato
Edi L.; Paulmichl
Markus; Dossena
Silvia
Abstract: Sequence alterations in the pendrin gene (SLC26A4) leading to functionally affected protein variants are frequently involved in the pathogenesis of syndromic and nonsyndromic deafness. Considering the high number of SLC26A4 sequence alterations reported to date, discriminating between functionally affected and unaffected pendrin protein variants is essential in contributing to determine the genetic cause of deafness in a given patient. In addition, identifying molecular features common to the functionally affected protein variants can be extremely useful to design future molecule-directed therapeutic approaches. Here we show the functional and molecular characterization of six previously uncharacterized pendrin protein variants found in a -cohort of 58 Brazilian deaf patients. Two variants (p.T193I and p.L445W) were undetectable in the plasma membrane, completely retained in the endoplasmic reticulum and showed no transport function; four (p.P142L, p.G149R, p.C282Y and p.Q413R) showed reduced function and significant, although heterogeneous, expression levels in the plasma membrane. Importantly, total expression levels of all of the functionally affected protein variants were significantly reduced with respect to the wild-type and a fully functional variant (p.R776C), regardless of their subcellular localization. Interestingly, reduction of expression may also reduce the transport activity of variants with an intrinsic gain of function (p.Q413R). As reduction of overall cellular abundance was identified as a common molecular feature of pendrin variants with affected function, the identification of strategies to prevent reduction in expression levels may represent a crucial step of potential future therapeutic interventions aimed at restoring the transport activity of dysfunctional pendrin variants.
Subject: Nonsyndromic Hearing-loss
Genotype-phenotype Correlation
Enlarged Vestibular Aqueduct
Endoplasmic-reticulum
Allelic Variants
Pds Gene
Molecular Analysis
Iodide Efflux
Inner-ear
Mutation
Editor: Feinsteins Ins Med Res
Manhasset
Rights: fechado
Identifier DOI: 10.2119/molmed.2015.00226
Address: http://molmed.org/articles/volume/item/23/34
Date Issue: 2016
Appears in Collections:Unicamp - Artigos e Outros Documentos

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