title: Congenital hypothyroidism with goitre caused by new mutations in the thyroglobulin gene.
abstract: BACKGROUND
  Thyroid dyshormonogenesis is associated with mutations in the thyroglobulin (TG) gene and characterized by normal organification of iodide and low serum TG. These mutations give rise to congenital goitrous hypothyroidism, transmitted in an autosomal recessive mode.
  
  
  OBJECTIVE
  The aim of this study was to identify new mutations in the TG gene in an attempt to increase the understanding of the molecular basis of this disorder. Three unrelated patients with marked impairment of TG synthesis were studied.
  
  
  METHODS
  The promoter and the complete coding regions of the TG gene, along with the flanking intronic regions, were analysed by direct DNA sequencing.
  
  
  RESULTS
  Four different inactivating TG mutations, three novel mutations (c.548G>A, p.C164Y; c.759-760insA, p.L234fsX237; c.6701C>A, p.A2215D) and one previously identified mutation (c.886C>T, p.R277X) were identified. Multiple sequence alignment study revealed that the wild-type cysteine residue at position 164 is strictly conserved in the TG of all the species analysed, whereas the wild-type alanine residue at position 2215 is well conserved in the TG and acetylcholinesterase (AChE) of all the species analysed except in rabbit AChE, in which it is substituted by glutamic acid.
  
  
  CONCLUSIONS
  We report three patients with congenital hypothyroidism with goitre caused by two compound heterozygous mutations, p.C164Y/p.L234fsX237 and p.R277X/p.A2215D, and one homozygous mutation, p.R277X, in the TG gene. To our knowledge this is the first report of the presence of a nucleotide insertion mutation in the TG gene.
authors.affiliation: Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Mariela
authors.initials: M
authors.lastname: Caputo
authors.forename: Carina M
authors.initials: CM
authors.lastname: Rivolta
authors.forename: Sebastían A
authors.initials: SA
authors.lastname: Esperante
authors.forename: Laura
authors.initials: L
authors.lastname: Gruñeiro-Papendieck
authors.forename: Ana
authors.initials: A
authors.lastname: Chiesa
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Pellizas
authors.forename: Rogelio
authors.initials: R
authors.lastname: González-Sarmiento
authors.forename: Héctor M
authors.initials: HM
authors.lastname: Targovnik
mesh_terms: D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006042:Goiter / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D017433:Protein Structure, Secondary; D013954:Thyroglobulin / Q000097:blood / Q000737:chemistry / Q000235:genetics*
chemical_list: D013954:Thyroglobulin