title: New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter.
abstract: BACKGROUND
  Thyroglobulin (TG) gene mutations cause congenital hypothyroidism (CH) with goiter. A founder effect has been proposed for some frequent mutations. Mutated proteins have a defect in intracellular transport causing intracellular retention with ultrastructural changes that resemble an endoplasmic reticulum storage disease.
  
  
  OBJECTIVE
  To reveal new aspects of thyroglobulin pathophysiology through clinical, cellular, molecular, and genetic studies in a family presenting with CH due to TG mutations from Galicia, an iodine-deficient area of Spain.
  
  
  METHODS
  The included clinical evaluation of family members, DNA sequencing for TG gene mutation and haplotyping analysis, ultrastructural analysis of thyroid tissue specimens from affected subjects, analysis of effects of mutations found on TG gene transcription, and in vitro studies of cellular production and secretion of mutated proteins.
  
  
  METHODS
  Locations included primary care and university hospitals.
  
  
  RESULTS
  Family members with CH, mental retardation, and goiter were compound heterozygous for c.886C-->T (p.R277X) and g.IVS35+1delG. For c.886C-->T, a founder effect cannot be excluded, and its transcription was hardly detectable. g.IVS35+1delG caused an in-frame deletion in exon 35 and produced a protein that, although synthesized, could not be secreted. Ultrastructural analyses showed morphological changes consistent with an endoplasmic reticulum storage disease.
  
  
  CONCLUSIONS
  The shorter thyroglobulin resulting from the novel g.IVS35+1delG was retained within the endoplasmic reticulum of thyrocytes, and together with p.R227X caused severe hypothyroidism with goiter. p.R277X, the most commonly described TG mutation, is caused by a TG exon-7 highly mutation-prone region, and the possibility that some cases were introduced to South America from Galicia cannot be excluded.
authors.affiliation: Unidade de Enfermedades Tiroideas e Metabolicas, School of Medicine, University of Santiago de Compostela, E-15782 Spain
authors.forename: D
authors.initials: D
authors.lastname: Peteiro-Gonzalez
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez-Fontan
authors.forename: I
authors.initials: I
authors.lastname: Castro-Piedras
authors.forename: J
authors.initials: J
authors.lastname: Cameselle-Teijeiro
authors.forename: A
authors.initials: A
authors.lastname: Beiras
authors.forename: S B
authors.initials: SB
authors.lastname: Bravo
authors.forename: C V
authors.initials: CV
authors.lastname: Alvarez
authors.forename: D M
authors.initials: DM
authors.lastname: Hardy
authors.forename: H M
authors.initials: HM
authors.lastname: Targovnik
authors.forename: P
authors.initials: P
authors.lastname: Arvan
authors.forename: J
authors.initials: J
authors.lastname: Lado-Abeal
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002478:Cells, Cultured; D003409:Congenital Hypothyroidism / Q000235:genetics*; D005820:Genetic Testing; D006042:Goiter / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D013030:Spain; D013954:Thyroglobulin / Q000235:genetics*
chemical_list: D013954:Thyroglobulin
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