title: Three mutations (p.Q36H, p.G418fsX482, and g.IVS19-2A>C) in the dual oxidase 2 gene responsible for congenital goiter and iodide organification defect.
abstract: BACKGROUND
  Iodide organification defects are associated with mutations in the dual oxidase 2 (DUOX2) gene and are characterized by a positive perchlorate discharge test. These mutations produce a congenital goitrous hypothyroidism, usually transmitted in an autosomal recessive mode.
  
  
  METHODS
  We studied the complete coding sequence of the human DUOX2 gene by single-strand conformational polymorphism (SSCP) analysis of DNA from 17 unrelated patients with iodide organification defects. Samples showing an aberrant pattern were directly sequenced. All mutations were validated by SSCP analysis. Finally, the effect of a splicing mutation was studied by construction of minigenes.
  
  
  RESULTS
  Genomic DNA sequencing revealed 3 novel mutations [c.108G>C (p.Q36H), c.1253delG (p.G418fsX482), and g.IVS19-2A>C] and 1 previously reported mutation [c.2895-2898delGTTC (p.S965fsX994)] in 2 families with 1 (family 1) and 2 (family 2) affected members. This implies the inheritance of 2 compound heterozygous mutations, p.Q36H and p.S965fsX994 in family 1 and p.G418fsX482 and g.IVS19-2A>C in family 2. The c.1253delG mutation was associated with a c.1254C>A transversion. In vitro transcription analysis showed that exon 20 is skipped entirely when the g.IVS19-2A>C mutation is present. The wild-type glutamine residue at position 36 is strictly conserved.
  
  
  CONCLUSIONS
  Two previously unknown compound heterozygous mutations in the DUOX2 gene, p.Q36H/p.S965fsX994 and p.G418fsX482/g.IVS19-2A>C, are responsible for iodide organification defects in 2 unrelated families. Identification of the molecular basis of this disorder might be helpful for understanding the pathophysiology of this congenital hypothyroidism.
authors.affiliation: Laboratorio de Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Viviana
authors.initials: V
authors.lastname: Varela
authors.forename: Carina M
authors.initials: CM
authors.lastname: Rivolta
authors.forename: Sebastián 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: Héctor M
authors.initials: HM
authors.lastname: Targovnik
mesh_terms: D000818:Animals; D001483:Base Sequence; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D000074623:Dual Oxidases; D005260:Female; D005420:Flavoproteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007454:Iodides / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D019255:NADPH Oxidases; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D012689:Sequence Homology, Nucleic Acid; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000378:metabolism*
chemical_list: D005420:Flavoproteins; D007454:Iodides; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human