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Context:  The DUOX/DUOXA systems play a key role in H 2 O 2  generation in thyroid cells, which is required for iodine organification and thyroid hormone synthesis. DUOX2/DUOXA2 defects can cause congenital hypothyroidism (CH), but it is unknown whether  DUOX1/DUOXA1  mutations can also cause CH.   Objective:  We aimed to identify  DUOX1/DUOXA1  mutations and explore their role in the development of CH by investigating their functional impacts on H 2 O 2  generation.   Patients and Methods:  Forty-three children with CH with goiter were enrolled, in whom all exons and flanking intronic regions of  DUOX1/DUOXA1  were directly sequenced. We characterized the functional effects of identified mutations on the expression of  DUOX1  and  DUOXA1  and H 2 O 2  generation.   Results:  We identified a heterozygous  DUOX1  missense mutation (G > A base substitution at nucleotide 3920 in exon 31) that changed a highly conserved arginine to glutamine at residual 1307 (p.R1307Q) in patient 1. A heterozygous-missense mutation (c.166 C>T; p.R56W) was identified in  DUOXA1  in patient 2. Functional studies demonstrated that both p.R1307Q mutant or p.R56W mutant decreased the  DUOX1  expression at mRNA and protein levels, with a corresponding impairment in H 2 O 2  generation ( P  < 0.01). The results also showed that intact DUOXA1 was required for full activity of DUOX1 and H 2 O 2  generation.   Conclusions:  We have identified two heterozygous missense mutations in  DUOX1  and  DUOXA1  in two patients that can cause CH through disrupting the coordination of DUOX1 and DUOXA1 in the generation of H 2 O 2 . This study for the first time demonstrates that the DUOX1/DUOXA1 system, if genetically defective, can cause CH.

frontiers in endocrinology

Identification of Two Missense Mutations in DUOX1 (p.R1307Q) and DUOXA1 (p.R56W) That Can Cause Congenital Hypothyroidism Through Impairing H2O2 Generation