DUOXA2 – Familial Thyroid Dyshormonogenesis

Thyroid dyshormonogenesis (TDH) is an autosomal recessive disorder characterized by defects at various steps of thyroid hormone biosynthesis, leading to congenital hypothyroidism (CH) (PMID:25231445). DUOXA2 encodes the maturation factor required for proper assembly, trafficking, and activity of the DUOX2 H₂O₂–generating complex at the apical membrane of thyrocytes.

Multiple unrelated families harbor biallelic DUOXA2 variants with clear recessive segregation. A Chinese patient homozygous for c.738C>G (p.Tyr246Ter) showed complete loss of DUOXA2 function and permanent CH (PMID:18042646). Another child with homozygous c.414C>G (p.Tyr138Ter) presented with CH that improved with age; her unaffected homozygous brother highlights variable expressivity (PMID:28626131). A third family carried compound heterozygous c.78C>G (p.Ile26Met)/c.738C>G (p.Tyr246Ter) and exhibited goitrous CH (PMID:25675383).

The DUOXA2 variant spectrum comprises nonsense (p.Tyr246Ter, p.Tyr138Ter), frameshift (c.95dup [p.Leu32fs]), and missense (p.Ile26Met) alleles, all absent or extremely rare in population databases. No recurrent founder alleles have been reported.

Functional studies confirm that p.Tyr246Ter truncates DUOXA2 before transmembrane helix 5, abrogating DUOX2 maturation and H₂O₂ production in vitro ([PMID:18042646]). The p.Ile26Met missense mutant displays normal expression but fails to support DUOX2 activity in HeLa cells ([PMID:25675383]). Cell-based assays and reconstituted DUOX/DUOXA co-expression models demonstrate that DUOXA2 is essential for DUOX2 apical localization and peroxidase coupling ([PMID:31172499]).

No studies have refuted the AR inheritance of DUOXA2-related TDH, and variable penetrance may reflect compensation by DUOXA1 or environmental factors. Additional large-scale screens have identified oligogenic patterns but confirm DUOXA2 as a primary driver in ~2–7% of TDH cases.

In summary, DUOXA2 is definitively implicated in autosomal recessive familial thyroid dyshormonogenesis through multiple families with biallelic loss-of-function variants and concordant functional impairment. Genetic testing of DUOXA2 informs diagnosis, prognosis, and genetic counseling in CH, and functional assays support variant classification.

References

• Endocrine development • 2014 • Clinical genetics of congenital hypothyroidism. PMID:25231445
• The Journal of clinical endocrinology and metabolism • 2008 • Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. PMID:18042646
• Endocrine journal • 2017 • Homozygous DUOXA2 mutation (p.Tyr138) in a girl with congenital hypothyroidism and her apparently unaffected brother: Case report and review of the literature.* PMID:28626131
• The Journal of clinical endocrinology and metabolism • 2015 • A novel missense mutation (I26M) in DUOXA2 causing congenital goiter hypothyroidism impairs NADPH oxidase activity but not protein expression. PMID:25675383
• Methods in molecular biology (Clifton, N.J.) • 2019 • DUOX Defects and Their Roles in Congenital Hypothyroidism. PMID:31172499

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