DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland

Kizys, Marina M. L.; Louzada, Ruy A.; Mitne‐Neto, Miguel; Jara, Jessica R; Furuzawa, Gilberto K.; Carvalho, Denise P.; Silva, Magnus R. Dias da; Nesi-França, Suzana; Dupuy, Corinne; Maciel, Rui M. B.

doi:10.1210/jc.2017-00832

Cited by 47 publications

(38 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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.…”

Section: Duox Defects In Congenital Hypothyroidismmentioning

confidence: 93%

“…With the development of next-generation sequencing techniques, analyses of multiple genetic alterations associated with CH-affected patients have been largely facilitated. 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].…”

Section: Duox Functional Characterization In Heterologous Cell Systemsmentioning

confidence: 99%

See 1 more Smart Citation

DUOX Defects and Their Roles in Congenital Hypothyroidism

Deken

Miot

2019

Methods in Molecular Biology

View full text Add to dashboard Cite

Extracellular hydrogen peroxide is required for thyroperoxidase-mediated thyroid hormone synthesis in the follicular lumen of the thyroid gland. Among the NADPH oxidases, dual oxidases, DUOX1 and DUOX2, constitute a distinct subfamily initially identified as thyroid oxidases, based on their level of expression in the thyroid. Despite their high sequence similarity, the two isoforms present distinct regulations, tissue expression, and catalytic functions. Inactivating mutations in many of the genes involved in thyroid hormone synthesis cause thyroid dyshormonogenesis associated with iodide organification defect. This chapter provides an overview of the genetic alterations in DUOX2 and its maturation factor, DUOXA2, causing inherited severe hypothyroidism that clearly demonstrate the physiological implication of this oxidase in thyroid hormonogenesis. Mutations in the DUOX2 gene have been described in permanent but also in transient forms of congenital hypothyroidism. Moreover, accumulating evidence demonstrates that the high phenotypic variability associated with altered DUOX2 function is not directly related to the number of inactivated DUOX2 alleles, suggesting the existence of other pathophysiological factors. The presence of two DUOX isoforms and their corresponding maturation factors in the same organ could certainly constitute an efficient redundant mechanism to maintain sufficient H 2 O 2 supply for iodide organification. Many of the reported DUOX2 missense variants have not been functionally characterized, their clinical impact in the observed phenotype remaining unresolved, especially in mild transient congenital hypothyroidism. DUOX2 function should be carefully evaluated using an in vitro assay wherein (1) DUOXA2 is co-expressed, (2) H 2 O 2 production is activated, (3) and DUOX2 membrane expression is precisely analyzed.

show abstract

Section: Duox Defects In Congenital Hypothyroidismmentioning

confidence: 93%

Section: Duox Functional Characterization In Heterologous Cell Systemsmentioning

confidence: 99%

DUOX Defects and Their Roles in Congenital Hypothyroidism

Deken

Miot

2019

Methods in Molecular Biology

View full text Add to dashboard Cite

show abstract

“…Despite the growing body of work in zebrafish aimed at understanding thyroid development, function and disease, there have been no reports describing the phenotypic consequences of duox mutations in adult zebrafish. This is despite the fact that mutations in DUOX2 and DUOX1 have been shown to be associated with congenital hypothyroidism in humans for more than a decade (Aycan et al, 2017;Donkó et al, 2014;Jin et al, 2014;Johnson et al, 2007;Kizys et al, 2017;Tonacchera et al, 2009;Vigone et al, 2005). Here, we describe the phenotypes associated with homozygosity of two lossof-function alleles of zebrafish duox in adult fish.…”

Section: Discussionmentioning

confidence: 93%

“…Ectopic thyroid glands have recently been reported in human DUOX2 mutations wherein scintigraphy revealed submandibular and sublingual thyroid ectopic locations (Kizys et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Congenital hypothyroidism (CH) is an endocrine disorder that may result from disrupted thyroid hormone (TH) synthesis (15-20% of all cases) or impaired development of the thyroid gland [thyroid dysgenesis (TD)] (80% of all cases) (Kizys et al, 2017). CH is the most prevalent congenital endocrine disorder and also believed to be one of the most preventable causes of mental retardation (Chakera et al, 2012;Olivieri, 2015;Roberts and Ladenson, 2004).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Zebrafishduoxmutations provide a model for human congenital hypothyroidism

Chopra

Ishibashi

Amaya

2018

Preprint

View full text Add to dashboard Cite

Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are the NADPH oxidase, DUOX1 and DUOX2. Indeed mutations in DUOX1 and DUOX2 have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue for DUOX1 and DUOX2. In this study, we investigated the phenotypes associated with two nonsense mutant alleles of the single duox gene in zebrafish, sa9892 and sa13017. Both alleles gave rise to readily observable phenotypes reminiscent of congenital hypothyroidism, from the larval stages through to adulthood. By using various methods to examine the external and internal phenotypes, we discovered a strong correlation between TH synthesis and duox function, beginning from the early larval stage, when T 4 levels are already noticeably absent in the mutants. Loss of T 4 production resulted in growth retardation, pigmentation defects, ragged fins, thyroid hyperplasia / external goiter, and infertility. Remarkably all of these defects associated with chronic congenital hypothyroidism could be rescued with T 4 treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafish duox mutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advance stages of development.

show abstract

Nicotinamide nucleotide transhydrogenase mutation analysis in Chinese patients with thyroid dysgenesis

Tian

Wang

et al. 2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Thyroid dysgenesis (TD) accounts for 80% cases of congenital hypothyroidism, which is the most common neonatal disorder. Until now, the gene mutations have been reported associated with TD can only account for 5% cases, suggesting the genetic heterogeneity of the pathology. Nicotinamide nucleotide transhydrogenase (NNT) plays a crucial role in regulating redox homeostasis, patients carrying NNT mutations have been described with a clinical phenotype of hypothyroidism. As TD risk is increased in the context of several syndromes and redox homeostasis is vital for thyroid development and function, NNT might be a candidate gene involved in syndromic TD. Therefore, we performed target sequencing (TS) in 289 TD patients for causative mutations in NNT and conducted functional analysis of the gene mutations. TS and Sanger sequence were used to screen the novel mutations. For functional analysis, we performed western blot, measurement of NADPH/NADPtotal and H2O2 generation, cell proliferation, and wounding healing assay. As a result, three presumably pathogenic mutations (c.811G > A, p.Ala271Ser; c.2078G > A, p.Arg693His; and c.2581G > A, p.Val861Met) in NNT had been identified. Our results showed the damaging effect of NNT mutations on stability and catalytic activity of proteins and redox balance of cells. In conclusion, our findings provided novel insights into the role of the NNT isotype in thyroid physiopathology and broaden the spectrum of pathogenic genes associated with TD. However, the pathogenic mechanism of NNT in TD is still need to be investigated in further study.

show abstract

DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland

Abstract: Our findings suggest that, in addition to thyroid hormonogenesis, the DUOX2 N-terminal domain may play a role in thyroid development.

Cited by 47 publications

References 38 publications

DUOX Defects and Their Roles in Congenital Hypothyroidism

DUOX Defects and Their Roles in Congenital Hypothyroidism

Zebrafishduoxmutations provide a model for human congenital hypothyroidism

Nicotinamide nucleotide transhydrogenase mutation analysis in Chinese patients with thyroid dysgenesis

Contact Info

Product

Resources

About