title: Identification of allelic variants of pendrin (SLC26A4) with loss and gain of function.
abstract: BACKGROUND
  Pendrin is a multifunctional anion transporter that exchanges chloride and iodide in the thyroid, as well as chloride and bicarbonate in the inner ear, kidney and airways. Loss or reduction in the function of pendrin results in both syndromic (Pendred syndrome) and non-syndromic (non-syndromic enlarged vestibular aqueduct (ns-EVA)) hearing loss. Factors inducing an up-regulation of pendrin in the kidney and the lung may have an impact on the pathogenesis of hypertension, chronic obstructive pulmonary disease (COPD) and asthma. Here we characterize the ion transport activity of wild-type (WT) pendrin and seven of its allelic variants selected among those reported in the single nucleotide polymorphisms data base (dbSNPs), some of which were previously identified in a cohort of individuals with normal hearing or deaf patients belonging to the Spanish population.
  
  
  METHODS
  WT and mutated pendrin allelic variants were functionally characterized in a heterologous over-expression system by means of fluorometric methods evaluating the I(-)/Cl(-) and Cl(-)/OH(-) exchange and an assay evaluating the efflux of radiolabeled iodide.
  
  
  RESULTS
  The transport activity of pendrin P70L, P301L and F667C is completely abolished; pendrin V609G and D687Y allelic variants are functionally impaired but retain significant transport. Pendrin F354S activity is indistinguishable from WT, while pendrin V88I and G740S exhibit a gain of function.
  
  
  CONCLUSIONS
  Amino acid substitutions involving a proline always result in a severe loss of function of pendrin. Two hyperfunctional allelic variants (V88I, G740S) have been identified, and they may have a contributing role in the pathogenesis of hypertension, COPD and asthma.
authors: Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria.
authors: Silvia
authors: S
authors: Dossena
authors: Aigerim
authors: A
authors: Bizhanova
authors: Charity
authors: C
authors: Nofziger
authors: Emanuele
authors: E
authors: Bernardinelli
authors: Josef
authors: J
authors: Ramsauer
authors: Peter
authors: P
authors: Kopp
authors: Markus
authors: M
authors: Paulmichl
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000838:Anions / Q000378:metabolism; D001249:Asthma / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D030541:Databases, Genetic; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000473:pathology; D017136:Ion Transport; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000473:pathology; D000076988:Sulfate Transporters
chemical_list: D000838:Anions; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters