Digenic DUOX1 and DUOX2 Mutations in Cases With Congenital Hypothyroidism

Abstract

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*); P1, P2: thyrotropin >100 µU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a 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 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.

Figure 1.

Pedigree diagram summarizing clinical phenotype and genotype. Black: homozygotes for the DUOX2 and DUOX1 mutations; central black dot: heterozygotes for the two mutations. The degree of iodine deficiency on the spot urinary measurement is classified according to World Health Organization criteria. DUOX1 fs, DUOX1 p.Val607Aspfs*43; het, heterozygous; hom, homozygous.

Figure 2.

Complementary DNA amplification and sequencing from homozygous and heterozygous family members, demonstrating aberrant splicing of DUOX1. The electropherogram of the complementary DNAs and transcript sizes of the different DUOX1 variants detected in the family members are shown. Exons are numbered with the first translated exon as exon 1. P1, P2: children with CH and homozygous DUOX1 c.1823-1G>C mutation. M, mother; F, father; S1, sister; all unaffected and heterozygous for the DUOX1 c.1823-1G>C mutation.