AUTHOR=Liu Shiguo , Han Wenxiu , Zang Yucui , Zang Hongwei , Wang Fang , Jiang Pei , Wei Hongwei , Liu Xiangju , Wang Yangang , Ma Xu , Ge Yinlin TITLE=Identification of Two Missense Mutations in DUOX1 (p.R1307Q) and DUOXA1 (p.R56W) That Can Cause Congenital Hypothyroidism Through Impairing H2O2 Generation JOURNAL=Frontiers in Endocrinology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00526 DOI=10.3389/fendo.2019.00526 ISSN=1664-2392 ABSTRACT=

Context: The DUOX/DUOXA systems play a key role in H₂O₂ 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 H₂O₂ 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 H₂O₂ 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 H₂O₂ generation (P < 0.01). The results also showed that intact DUOXA1 was required for full activity of DUOX1 and H₂O₂ 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 H₂O₂. This study for the first time demonstrates that the DUOX1/DUOXA1 system, if genetically defective, can cause CH.