title: Sodium/Iodide Symporter Mutant V270E Causes Stunted Growth but No Cognitive Deficiency.
abstract: BACKGROUND
  Iodide (I(-)), an essential constituent of the thyroid hormones, is actively accumulated in the thyroid by the Na(+)/I(-) symporter (NIS), a key plasma membrane protein encoded by the slc5a5 gene. Mutations in slc5a5 cause I(-) transport defects (ITDs), autosomal-recessive disorders in which I(-) accumulation is totally or partially impaired, leading to congenital hypothyroidism. The characterization of NIS mutants has yielded significant insights into the molecular mechanism of NIS.
  
  
  OBJECTIVE
  This study aimed to determine the basis of a patient's ITD clinical phenotype, by sequencing her slc5a5 gene.
  
  
  METHODS
  Genomic DNA was purified and the slc5a5 gene sequence determined. Functional in vitro studies were performed to characterize the V270E NIS mutant.
  
  
  METHODS
  The index patient was diagnosed with hypothyroidism with minimal radioiodide uptake in a normally located, although enlarged, thyroid gland.
  
  
  RESULTS
  We identified a new NIS mutation: V270E. The patient had the compound heterozygous NIS mutation R124H/V270E. R124H NIS has been characterized previously. We show that V270E markedly reduces I(-) uptake via a pronounced (but not total) impairment of the protein's plasma membrane targeting. Remarkably, V270E is intrinsically active. Therefore, a negative charge at position 270 interferes with NIS cell surface trafficking. The patient's minimal I(-) uptake enabled sufficient thyroid hormone biosynthesis to prevent cognitive impairment.
  
  
  CONCLUSIONS
  A nonpolar residue at position 270, which all members of the SLC5A family have, is required for NIS plasma membrane targeting.
authors.affiliation: Department of Cellular and Molecular Physiology (J.P.N., A.R.-N., N.C.), Yale University School of Medicine, New Haven, Connecticut 06510; Department of Pediatrics (P.S., J.D.G.G.), Winthrop-University Hospital, Mineola, New York 11501; Department of Genetics (D.F.R.-B.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pediatrics (R.M.), Albert Einstein College of Medicine, Bronx, New York 10467; and Department of Biophysics and Biophysical Chemistry (L.M.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Nicola
authors.affiliation: Department of Cellular and Molecular Physiology (J.P.N., A.R.-N., N.C.), Yale University School of Medicine, New Haven, Connecticut 06510; Department of Pediatrics (P.S., J.D.G.G.), Winthrop-University Hospital, Mineola, New York 11501; Department of Genetics (D.F.R.-B.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pediatrics (R.M.), Albert Einstein College of Medicine, Bronx, New York 10467; and Department of Biophysics and Biophysical Chemistry (L.M.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Andrea
authors.initials: A
authors.lastname: Reyna-Neyra
authors.affiliation: Department of Cellular and Molecular Physiology (J.P.N., A.R.-N., N.C.), Yale University School of Medicine, New Haven, Connecticut 06510; Department of Pediatrics (P.S., J.D.G.G.), Winthrop-University Hospital, Mineola, New York 11501; Department of Genetics (D.F.R.-B.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pediatrics (R.M.), Albert Einstein College of Medicine, Bronx, New York 10467; and Department of Biophysics and Biophysical Chemistry (L.M.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Paul
authors.initials: P
authors.lastname: Saenger
authors.affiliation: Department of Cellular and Molecular Physiology (J.P.N., A.R.-N., N.C.), Yale University School of Medicine, New Haven, Connecticut 06510; Department of Pediatrics (P.S., J.D.G.G.), Winthrop-University Hospital, Mineola, New York 11501; Department of Genetics (D.F.R.-B.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pediatrics (R.M.), Albert Einstein College of Medicine, Bronx, New York 10467; and Department of Biophysics and Biophysical Chemistry (L.M.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: David F
authors.initials: DF
authors.lastname: Rodriguez-Buritica
authors.affiliation: Department of Cellular and Molecular Physiology (J.P.N., A.R.-N., N.C.), Yale University School of Medicine, New Haven, Connecticut 06510; Department of Pediatrics (P.S., J.D.G.G.), Winthrop-University Hospital, Mineola, New York 11501; Department of Genetics (D.F.R.-B.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pediatrics (R.M.), Albert Einstein College of Medicine, Bronx, New York 10467; and Department of Biophysics and Biophysical Chemistry (L.M.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: José David
authors.initials: JD
authors.lastname: Gamez Godoy
authors.affiliation: Department of Cellular and Molecular Physiology (J.P.N., A.R.-N., N.C.), Yale University School of Medicine, New Haven, Connecticut 06510; Department of Pediatrics (P.S., J.D.G.G.), Winthrop-University Hospital, Mineola, New York 11501; Department of Genetics (D.F.R.-B.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pediatrics (R.M.), Albert Einstein College of Medicine, Bronx, New York 10467; and Department of Biophysics and Biophysical Chemistry (L.M.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
authors.affiliation: Department of Cellular and Molecular Physiology (J.P.N., A.R.-N., N.C.), Yale University School of Medicine, New Haven, Connecticut 06510; Department of Pediatrics (P.S., J.D.G.G.), Winthrop-University Hospital, Mineola, New York 11501; Department of Genetics (D.F.R.-B.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pediatrics (R.M.), Albert Einstein College of Medicine, Bronx, New York 10467; and Department of Biophysics and Biophysical Chemistry (L.M.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: L Mario
authors.initials: LM
authors.lastname: Amzel
authors.affiliation: Department of Cellular and Molecular Physiology (J.P.N., A.R.-N., N.C.), Yale University School of Medicine, New Haven, Connecticut 06510; Department of Pediatrics (P.S., J.D.G.G.), Winthrop-University Hospital, Mineola, New York 11501; Department of Genetics (D.F.R.-B.), University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pediatrics (R.M.), Albert Einstein College of Medicine, Bronx, New York 10467; and Department of Biophysics and Biophysical Chemistry (L.M.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Nancy
authors.initials: N
authors.lastname: Carrasco
mesh_terms: D000483:Alleles; D002648:Child; D003072:Cognition Disorders / Q000235:genetics*; D003409:Congenital Hypothyroidism / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D027981:Symporters / Q000235:genetics*; D000099209:Sodium-Iodide Symporters
chemical_list: D027981:Symporters; D000099209:Sodium-Iodide Symporters