Digenic DUOX1 and DUOX2 mutations in cases with congenital hypothyroidism

01 Aug 2017

Context: The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the TPO-catalyzed iodination and coupling reactions mediating thyroid hormone biosynthesis. DUOX2 mutations result in dyshormonogenetic Congenital Hypothyroidism (CH) which may be phenotypically heterogeneous, leading to the hypothesis that CH severity may be influenced by environmental factors (eg dietary iodine) and oligogenic modifiers (eg variants in the homologous NADPH-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*); P1, P2: TSH >100 µU/mL (reference range, RR: 0.5-6.3), P1: Free T4 (FT4) <0.09 ng/dl (RR: 0.9-2.3). Subsequent studies have revealed a novel, homozygous DUOX1 mutation (c.1823-1G>C) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43) which segregates with CH in this kindred. Conclusion: This is the first 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 novel digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically-ascertained CH.