title: A novel missense mutation (I26M) in DUOXA2 causing congenital goiter hypothyroidism impairs NADPH oxidase activity but not protein expression.
abstract: BACKGROUND
  Dual-oxidase maturation factor 2 (DUOXA2) is a component of the thyroid hydrogen peroxidase (H2O2) generator, which is crucial for hormone synthesis. Genetic defects in DUOXA2 lead to an impairment of the H2O2-generating system, in turn causing congenital hypothyroidism (CH) with goiter.
  
  
  METHODS
  Our study aimed to identify DUOXA2 mutations associated with Chinese congenital goiter hypothyroidism patients and to examine the molecular mechanism underlying the genotype-phenotype relationship. All exons and flanking sequences of DUOXA2 in 75 unrelated CH with goiter patients were amplified by PCR and directly sequenced. DUOXA2 and DUOX2 protein expression levels were detected by Western blotting, and nicotinamide adenine dinucleotide phosphate oxidase activity was determined by measuring H2O2 generation in HeLa cells. A novel heterozygous missense mutation, c.C78G (p.I26M), and a homozygous nonsense mutation, c.C738G (p.Y246X), in DUOXA2 were identified in CH patients with mild transient and mild permanent goiter, respectively. In vitro experiments showed that the mutant I26M protein expression levels did not differ from those of wild-type DUOXA2 but that mutant I26M resulted in a complete deficiency of H2O2 generation.
  
  
  CONCLUSIONS
  We identified a novel DUOXA2 mutation (I26M) causing CH with goiter, which affected H2O2 generation but did not alter the protein expression levels, further confirming the essential role of DUOXA2 in thyroid hormone synthesis.
authors: Prenatal Diagnosis Center (S.L.), Genetic Laboratory (S.L.), and Departments of Endocrinology (L.L., S.Y.) and Ultrasonography (X.N.), The Affiliated Hospital of Qingdao University, Qingdao 266003, China; Department of Clinical Laboratory (D.L.), Linyi People's Hospital, Shandong University, Linyi 276003, China; Graduate School (H.X.), Peking Union Medical College, Beijing 100730, China; and World Health Organization Collaborating Centre for Research in Human Reproduction (H.X.), and National Research Institute for Family Planning (H.X.), Beijing 100081, China.
authors: Shiguo
authors: S
authors: Liu
authors: Lu
authors: L
authors: Liu
authors: Xiaoyan
authors: X
authors: Niu
authors: Deguo
authors: D
authors: Lu
authors: Hongfei
authors: H
authors: Xia
authors: Shengli
authors: S
authors: Yan
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006042:Goiter / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007532:Isoleucine / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008715:Methionine / Q000235:genetics; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism
chemical_list: C513411:DUOXA2 protein, human; D008565:Membrane Proteins; D007532:Isoleucine; D008715:Methionine; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases