Compound Heterozygous Mutations in theDUOX2/DUOXA2Genes Cause Congenital Hypothyroidism

Abstract

The mutations in the dual oxidase 2 (DUOX2) and dual oxidase maturation factor 2 (DUOXA2) genes can cause congenital hypothyroidism (CH). This study reports the pedigree with goitrous congenital hypothyroidism (GCH) due to the coexistence of heterozygous mutations in the DUOX2 and DUOXA2 genes. The two sisters with GCH were diagnosed with CH at neonatal screening and were enrolled in this study. The DUOX2, DUOXA2, and thyroid peroxidase (TPO) genes were considered for genetic defects screening. Family members of the patients and normal controls were also enrolled and evaluated. The two girls harbored compound heterozygous mutations, including a new mutation of c.2654G>T (p.R885L) in the maternal DUOX2 allele and c.738C>G (p.Y246X) in the paternal DUOXA2 allele, that has been previously reported. The germline mutations from the families were consistent with an autosomal recessive inheritance pattern. No mutations in the TPO gene and the controls were observed.

DUOX Defects and Their Roles in Congenital Hypothyroidism

“…We have completed their extensive analysis of the literature with [75,85]). PIOD partial iodide organification defect, TIOD total iodide organification defect additional reported cases of novel DUOX2/DUOXA2 deficient patients [102][103][104][105][106][107][108][109][110][111]. In summary and to the best of our knowledge, about 105 DUOX2 variants including in-frame deletions, missense, nonsense, splice site, and frameshift mutations have been described in more than 200 unrelated CH patients.…”

“…Six missense, two nonsense, and two splice site mutations have been described (Fig. 5B) [69,105,107,109,[120][121][122][123][124][125]. The first homozygous missense p.Y246X mutation was reported in 2008 in a Chinese patient suffering from a mild permanent CH [69].…”

“…The first homozygous missense p.Y246X mutation was reported in 2008 in a Chinese patient suffering from a mild permanent CH [69]. This mutation has been reported in four additional cases but with various severities in the clinical outcome [107,121,122,124]. Intrafamilial variabilities have also been reported for DUOXA2-affected patients.…”

“…The coexistence of multiple genetic alterations in the DUOX2 gene such as tri-allelic mutations has been associated with an increase in the severity of the disease [106,112,113]. In addition, increasing number of clinical case studies report DUOX2 pathogenic variants concomitant with genetic alterations in other genes involved in TH synthesis including TG [125,127], TSHr [102,109,118,132], TPO [133], Pendrin [115], and DUOXA2 [107,123]. Additional studies would clarify their functional relevance in the evolution of the pathology.…”

DUOX2, a new player on the scene of thyroid hormones

“…Other studies associated OS with both hyperthyroidism and hypothyroidism however, the mechanisms are different: low availability of antioxidants in hypothyroidism and increased ROS production in hyperthyroidism. It is demonstrated in many studies the involvement of OS in numerous pathologies, and thyroid disorders are among them (12,13). Some hyperthyroidism complications in target tissues are caused by OS (14,15).…”