WOS: 000409352800001 PubMed ID: 28633507 Context: The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the thyroid peroxidase-catalyzed iodination and coupling reactions mediating thyroid hormone biosynthesis. DUOX2 mutations result in dyshormonogenetic congenital hypothyroidism (CH) that may be phenotypically heterogeneous, leading to the hypothesis that CH severity may be influenced by environmental factors (e.g., dietary iodine) and oligogenic modifiers (e.g., variants in the homologous reduced form of NAD phosphate-oxidase DUOX1). However, loss-of-function mutations in DUOX1 have not hitherto been described, and its role in thyroid biology remains undefined. Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (p.R434(star)); P1, P2: thyrotropin >100 mu U/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) C) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs(star)43), which segregates with CH in this kindred. Conclusion: This is a report of digenic mutations in DUOX1 and DUOX2 in association with CH, and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype. Our studies provide evidence for a digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically ascertained CH. Wellcome Trust [100585/Z/12/Z, 095564/Z/11/Z]; National Institutes for Health Research Cambridge Biomedical Research Centre; Italian Ministry of Health [RF-2010-2309484]; TUBITAK: The Scientific and Technological Research Council of Turkey [214S637] This work was supported by Wellcome Trust Grants 100585/Z/12/Z (to N.S.) and 095564/Z/11/Z (to V.K.C.); National Institutes for Health Research Cambridge Biomedical Research Centre (to V.K.C. and N.S.); and Italian Ministry of Health Grant RF-2010-2309484 (to L.P.). H.C. is supported by TUBITAK: The Scientific and Technological Research Council of Turkey Grant 214S637.
