DUOXA2, also known as dual oxidase maturation factor 2, is a crucial factor for the maturation and activation of dual oxidase DUOX2, a member of the NADPH oxidase family. It aids DUOX2 in correctly migrating from the endoplasmic reticulum to the plasma membrane, and together they form a stable complex promoting hydrogen peroxide (H2O2) generation in thyroid hormone synthesis [2].

Genetic alterations in DUOXA2 lead to defective function of DUOX2 protein, causing inherited congenital hypothyroidism (CH) [2]. In a cohort of 377 CH cases, DUOXA2 was prominent in thyroid dysgenesis (TD) cases (18.75%) [1]. A study reported a nonsense DUOXA2 mutation (p.Tyr138*) in a girl with congenital hypothyroidism and her apparently unaffected brother, and expression experiments in HEK293 cells confirmed it as a loss-of-function mutation, suggesting a broader phenotypic spectrum of DUOXA2 mutations [3]. In a cross-sectional study of borderline CH cases, 6 out of 52 patients (12%) harbored likely pathogenic mutations in DUOXA2, including novel gene variants [4].

In conclusion, DUOXA2 is essential for thyroid hormone synthesis through its role in DUOX2 activation. Mutations in DUOXA2 are associated with congenital hypothyroidism, including in TD and borderline CH cases. The study of DUOXA2 mutations in such disease conditions helps in understanding the genetic basis of congenital hypothyroidism and potentially improving diagnosis and treatment strategies.

References:

1. Wang, Fengqi, Zang, Yucui, Li, Miaomiao, Wang, Fang, Liu, Shiguo. 2020. DUOX2 and DUOXA2 Variants Confer Susceptibility to Thyroid Dysgenesis and Gland-in-situ With Congenital Hypothyroidism. In Frontiers in endocrinology, 11, 237. doi:10.3389/fendo.2020.00237. https://pubmed.ncbi.nlm.nih.gov/32425884/

2. Du, Jiani, Yang, Yanling, Wei, Ding, Cheng, Chen, Zhai, Xiaoyan. 2024. The role of DUOXA2 in the clinical diagnosis of paediatric congenital hypothyroidism. In Annals of medicine, 57, 2440121. doi:10.1080/07853890.2024.2440121. https://pubmed.ncbi.nlm.nih.gov/39673194/

3. Sugisawa, Chiho, Higuchi, Shinji, Takagi, Masaki, Hasegawa, Tomonobu, Narumi, Satoshi. 2017. Homozygous DUOXA2 mutation (p.Tyr138*) in a girl with congenital hypothyroidism and her apparently unaffected brother: Case report and review of the literature. In Endocrine journal, 64, 807-812. doi:10.1507/endocrj.EJ16-0564. https://pubmed.ncbi.nlm.nih.gov/28626131/

4. Peters, Catherine, Nicholas, Adeline K, Schoenmakers, Erik, Fugazzola, Laura, Schoenmakers, Nadia. . DUOX2/DUOXA2 Mutations Frequently Cause Congenital Hypothyroidism that Evades Detection on Newborn Screening in the United Kingdom. In Thyroid : official journal of the American Thyroid Association, 29, 790-801. doi:10.1089/thy.2018.0587. https://pubmed.ncbi.nlm.nih.gov/31044655/