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

The DUOX/DUOXA systems play a key role in HO 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 mutations can also cause CH. We aimed to identify mutations and explore their role in the development of CH by investigating their functional impacts on HO generation. Forty-three children with CH with goiter were enrolled, in whom all exons and flanking intronic regions of were directly sequenced. We characterized the functional effects of identified mutations on the expression of and and HO generation. We identified a heterozygous 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 in patient 2. Functional studies demonstrated that both p.R1307Q mutant or p.R56W mutant decreased the expression at mRNA and protein levels, with a corresponding impairment in HO generation ( < 0.01). The results also showed that intact DUOXA1 was required for full activity of DUOX1 and HO generation. We have identified two heterozygous missense mutations in and in two patients that can cause CH through disrupting the coordination of DUOX1 and DUOXA1 in the generation of HO. This study for the first time demonstrates that the DUOX1/DUOXA1 system, if genetically defective, can cause CH.