title: Mapping pathogenic mutations suggests an innovative structural model for the pendrin (SLC26A4) transmembrane domain.
abstract: 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.
authors: Dept. of Biomedical Sciences, CRIBI Biotechnology Center, University of Padua, Italy.
authors: Claudio
authors: C
authors: Bassot
authors: Dept. of Biomedical Sciences, CRIBI Biotechnology Center, University of Padua, Italy.
authors: Giovanni
authors: G
authors: Minervini
authors: Dept. of Woman and Child Health, University of Padua, Italy.
authors: Emanuela
authors: E
authors: Leonardi
authors: Dept. of Biomedical Sciences, CRIBI Biotechnology Center, University of Padua, Italy; CNR Institute of Neuroscience, Padua, Italy. Electronic address: silvio.tosatto@unipd.it.
authors: Silvio C E
authors: SC
authors: Tosatto
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006044:Goiter, Nodular / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D000076988:Sulfate Transporters; D014723:Vestibular Aqueduct / Q000002:abnormalities
chemical_list: D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters
keywords: Homology modeling; Mutation mapping; Non-syndromic hearing loss with enlarged vestibular aqueduct (ns-EVA); Pendred syndrome; Pendrin; SLC26A4; Transmembrane protein