Human pendrin (SLC26A4) is an anion transporter mostly expressed in the inner ear, thyroid and kidney. SLC26A4 gene mutations are associated with a broad phenotypic spectrum, including Pendred Syndrome and non-syndromic hearing loss with enlarged vestibular aqueduct (ns-EVA). No experimental structure of pendrin is currently available, making phenotype-genotype correlations difficult as predictions of transmembrane (TM) segments vary in number. Here, we propose a novel three-dimensional (3D) pendrin transmembrane domain model based on the SLC26Dg transporter. The resulting 14 TM topology was found to include two non-canonical transmembrane segments crucial for pendrin activity. Mutation mapping of 147 clinically validated pathological mutations shows that most affect two previously undescribed TM regions.
Keywords: Homology modeling; Mutation mapping; Non-syndromic hearing loss with enlarged vestibular aqueduct (ns-EVA); Pendred syndrome; Pendrin; SLC26A4; Transmembrane protein.
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