title: Pendred syndrome in two Galician families: insights into clinical phenotypes through cellular, genetic, and molecular studies.
abstract: BACKGROUND
  We studied two families from Galicia (northwest Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T3 (FT3). In family B, some affected members showed deafness but not goiter.
  
  
  OBJECTIVE
  Our objective was to identify the mutations causing PS and molecular mechanisms underlying the thyroid phenotypes.
  
  
  METHODS
  Interventions included extraction of DNA and of thyroid tissue.
  
  
  METHODS
  Propositi and 10 members of the two families participated in the study.
  
  
  METHODS
  Main outcome measures included SLC26A4 gene analysis, deiodinase activities in thyroid tissue, and c.416-1G-->A effects on SLC26A4 splicing. In addition, a primary PS thyrocyte culture, T-PS2, was obtained from propositus B and compared with another culture of normal human thyrocytes, NT, by Western blotting, confocal microscopy, and iodine uptake kinetics.
  
  
  RESULTS
  Proposita A was heterozygous for c.578C-->T and c.279delT, presented with goiter, and had normal TSH and FT3 but low FT4 attributable to high type 1 and type 2 iodothyronine deiodinase activities in the goiter. Propositus B bore c.279delT and a novel mutation c.416-1G-->A; some deaf relatives were homozygous for c.416-1G-->A but did not present goiter. The c.279delT mutation was associated with identical haplotype in the two families. T-PS2 showed truncated pendrin retained intracellularly and high iodine uptake with low efflux leading to iodine retention.
  
  
  CONCLUSIONS
  c.279delT is a founder mutation in Galicia. Proposita A adapted to poor organification by increasing deiodinase activities in the goiter, avoiding hypothyroidism. Lack of goiter in subjects homozygous for c.416-1G-->A was due to incomplete penetrance allowing synthesis of some wild-type pendrin. Intracellular iodine retention, as seen in T-PS2, could play a role in thyroid alterations in PS.
authors.affiliation: Unidade de Enfermedades Tiroideas e Metabólicas, Department of Medicine, University of Santiago de Compostela, C/ San Francisco sn, Santiago de Compostela 15705, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Palos
authors.forename: María E R
authors.initials: ME
authors.lastname: García-Rendueles
authors.forename: David
authors.initials: D
authors.lastname: Araujo-Vilar
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Obregon
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Calvo
authors.forename: Jose
authors.initials: J
authors.lastname: Cameselle-Teijeiro
authors.forename: Susana B
authors.initials: SB
authors.lastname: Bravo
authors.forename: Oscar
authors.initials: O
authors.lastname: Perez-Guerra
authors.forename: Lourdes
authors.initials: L
authors.lastname: Loidi
authors.forename: Barbara
authors.initials: B
authors.lastname: Czarnocka
authors.forename: Paula
authors.initials: P
authors.lastname: Alvarez
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Lourdes
authors.initials: L
authors.lastname: Dominguez-Gerpe
authors.forename: Clara V
authors.initials: CV
authors.lastname: Alvarez
authors.forename: Joaquin
authors.initials: J
authors.lastname: Lado-Abeal
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D005260:Female; D006044:Goiter, Nodular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006239:Haplotypes; D006319:Hearing Loss, Sensorineural / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007453:Iodide Peroxidase / Q000096:biosynthesis / Q000235:genetics; D007455:Iodine / Q000493:pharmacokinetics; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis / Q000235:genetics; D010375:Pedigree; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013030:Spain; D000076988:Sulfate Transporters; D027981:Symporters; D013577:Syndrome; D013960:Thyroid Function Tests; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D007455:Iodine; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; D000076988:Sulfate Transporters; D027981:Symporters; D000097564:Iodothyronine Deiodinase Type II; C090735:SLC16A2 protein, human; C085609:SLC26A4 protein, human; C109812:iodothyronine deiodinase type I