Three Mutations (p.Q36H, p.G418fsX482 and g.IV19-2A>C) in the Dual Oxidase 2 (DUOX2) Gene Responsible for Congenital Goiter and Iodide Organification Defect.

VIVIANA VARELA; CARINA M. RIVOLTA; SEBASTIÁN A. ESPERANTE; LAURA GRUÑEIRO-PAPENDIECK; ANA CHIESA; HÉCTOR M. TARGOVNIK

CLINICAL CHEMISTRY

American Association for Clinical Chemistry

Lugar: Washington DC; Año: 2006 vol. 52 p. 182 - 191

0009-9147

Background: Iodide organification defects are associated with  mutations in the dual oxidase 2 (DUOX2) gene  and characterized by a positive perchlorate discharge test. These mutations originate a congenital goitrous hypothyroidism, transmitted ussually in an autosomal recessive mode. Methods: The complete coding sequence of the human DUOX2 gene was studied by single stranded conformational polymorphism (SSCP) analysis from 17 unrelated patients with iodide organification defect. Samples showing an aberrant pattern were directly sequenced. All mutations were validated by SSCP. Finally, the effect of a splicing mutation was studied by construction of minigenes. Results: Genomic DNA sequencing revealed three novel mutations, c.108G>C (p.Q36H), c.1253delG (p.G418fsX482) and g.IV19-2A>C, and one previously reported, c.2895-2898delGTTC (p.S965fsX994) in two families with one (family 1) and two (family 2) affected members. This implies the inheritance of two compound heterozygous mutations, p.Q36H and p.S965fsX994 in family 1 and p.G418fsX482 and g.IV19-2A>C in family 2. The c.1253delG mutation was found associated with a c.1254C>A transversion.  In vitro transcription analysis showed that the exon 20 is skipped entirely when the g.IV19-2A>C mutation is present. The wild-type glutamine residue at position 36 is strictly conserved. Conclusions: We have reported two unrelated families with iodide organification defect caused by two compound heterozygous mutations, p.Q36H/ p.S965fsX994 and p.G418fsX482/g.IV19-2A>C, in the DUOX2 gene. Identification of the molecular basis of this disorder might be helpful for understanding the pathophysiology of this congenital hypothyroidism.