DUOX2 – Familial Thyroid Dyshormonogenesis

Familial thyroid dyshormonogenesis is an autosomal recessive disorder (MONDO:0010132) characterized by defects in thyroid hormone synthesis despite a structurally normal gland. DUOX2 (HGNC:13273) encodes dual oxidase 2, a NADPH‐oxidase producing H₂O₂ at the apical membrane of thyrocytes, essential for iodide organification and thyroid hormone biosynthesis.

Extensive genetic studies in thyroid dyshormonogenesis cohorts have established a strong association between biallelic or monoallelic DUOX2 variants and disease. In a Guangzhou population‐based cohort of 96 patients with suspected dyshormonogenesis, 60 unrelated individuals harbored 23 distinct DUOX2 variants (60/96) (PMID:27557340). In a Japanese DH series of 21 patients, 17 (81%) carried DUOX2 mutations, including both novel and recurrent alleles (PMID:30154845). Segregation analysis in affected sibships further supports autosomal recessive inheritance and co‐segregation of DUOX2 variants with thyroid dyshormonogenesis (2 affected relatives).

The DUOX2 variant spectrum includes nonsense, frameshift, missense, splice‐site, and small in‐frame deletions. Recurrent alleles include c.1588A>T (p.Lys530Ter) and c.3329G>A (p.Arg1110Gln), with population‐specific founder effects observed for p.Lys530Ter in East Asian cohorts. Functional SNPs such as p.His678Arg modulate phenotypic severity when present in trans with loss‐of‐function alleles.

Functional assays in vitro demonstrate that DUOX2 loss‐of‐function variants impair H₂O₂ generation and proper trafficking. The compound heterozygous mutations p.Q36H and p.Gly418AlafsTer (c.1253del) abolish iodide organification in minigene and cell‐based assays (PMID:16322276). Missense variants Q36H and R376W prevent ER exit and cell‐surface expression in DUOXA2‐reconstituted systems, confirming their pathogenicity (PMID:17374849).

No significant conflicting evidence has been reported; genotype–phenotype correlation shows that biallelic loss‐of‐function alleles typically cause permanent congenital hypothyroidism, whereas monoallelic or hypomorphic variants may underlie transient forms.

In summary, DUOX2 meets criteria for a definitive gene‐disease association in familial thyroid dyshormonogenesis with robust genetic evidence from large cohorts and concordant functional validation. Key take‐home: DUOX2 mutation screening is clinically actionable for diagnosis, genetic counseling, and personalized management of thyroid dyshormonogenesis.

References

• Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme • 2016 • The Prevalence, Clinical, and Molecular Characteristics of Congenital Hypothyroidism Caused by DUOX2 Mutations: A Population-Based Cohort Study in Guangzhou PMID:27557340
• International journal of endocrinology • 2018 • Mutational Spectrum Analysis of Seven Genes Associated with Thyroid Dyshormonogenesis PMID:30154845
• Clinical chemistry • 2006 • Three mutations (p.Q36H, p.G418fsX482, and g.IVS19-2A>C) in the dual oxidase 2 gene responsible for congenital goiter and iodide organification defect PMID:16322276
• Molecular endocrinology (Baltimore, Md.) • 2007 • Missense mutations of dual oxidase 2 (DUOX2) implicated in congenital hypothyroidism have impaired trafficking in cells reconstituted with DUOX2 maturation factor PMID:17374849

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