Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2

Yoshizawa-Ogasawara, Atsuko; Abe, Kodai; Ogikubo, Sayaka; Narumi, Shunji; Hasegawa, Tomonobu; Satoh, Mari

doi:10.1515/jpem-2014-0479

Cited by 14 publications

(10 citation statements)

References 13 publications

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“…A recent report revealed that the combination of biallelic mutation in DUOX2 with the monoallelic mutation in a different thyroid hormone-generating enzyme might cause CH. (35). However in some cases, the combination of biallelic mutation in DUOX2 with the monoallelic mutation in a Supply of H 2 O 2 production Figure 2 The proposed mechanism underlying the development of transient CH due to DUOX2 defects.…”

Section: Discussionmentioning

confidence: 99%

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

Maruo

Nagasaki

Matsui

et al. 2016

European Journal of Endocrinology

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Aim: We previously reported that biallelic mutations in dual oxidase 2 (DUOX2) cause transient hypothyroidism.Since then, many cases with DUOX2 mutations have been reported. However, the clinical features and prognosis of individuals with DUOX2 defects have not been clarified. Objective: We investigated the prognosis of patients with congenital hypothyroidism (CH) due to DUOX2 mutations. Patients: Twenty-five patients were identified by a neonatal screening program and included seven familial cases. Their serum TSH values ranged from 18.9 to 734.6 mU/l. Twenty-two of the patients had low serum free thyroxine (fT 4 ) levels (0.17-1.1 ng/dl). Twenty-four of the patients were treated with L-thyroxine. Methods: We analyzed the DUOX2, thyroid peroxidase, Na C /I K symporter, and dual oxidase maturation factor 2 genes of these 25 patients by PCR-amplified direct sequencing. An additional 11 genes were analyzed in 11 of the 25 patients using next-generation sequencing. Results: All patients had biallelic DUOX2 mutations, and seven novel alleles were detected. Fourteen of the patients were able to discontinue replacement therapy, and seven were receiving reduced L-thyroxine doses. Normalization of thyroglobulin lagged several years behind the completion of treatment. Two patients showed permanent hypothyroidism. Except for one case of a learning disability, growth and psychomotor development were normal. Conclusion: The prognosis of Japanese patients with DUOX2 defects was usually transient CH. Delayed improvement of thyroglobulin indicates that these patients have subclinical hypothyroidism. Hypothyroidism did not recur in patients during the study period (up to 18 years old).

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Section: Discussionmentioning

confidence: 99%

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

Maruo

Nagasaki

Matsui

et al. 2016

European Journal of Endocrinology

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“…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.…”

Section: Duox Functional Characterization In Heterologous Cell Systemsmentioning

confidence: 99%

“…Moreover, as the basal activity of the oxidase is very low, agents increasing the intracellular Ca 2+ concentration must be added in the assay. The calcium ionophore ionomycin [55,106,110,116,[133][134][135] and the Ca 2+ -ATPase inhibitor thapsigargin [104,111] have been successfully used in different assays. The cell type could also modify the final outcome of the assay in terms of activity or maturation of the protein.…”

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

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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.

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“…This phenotypic or genetic heterogeneity suggests that mono-and polygenic factors and environmental modulators have roles in the determination of disease severity (4,5). Some cases have oligogenic mutations apart from single-gene mutations and demonstrate heterogeneous phenotypes to those carrying monogenic mutations (15)(16)(17). These cases may not be inherited in a monogenic manner; that is, a digenic or oligogenic inheritance may be considered, or mutations may occur, acting as a genetic modifiers (18,19).…”

Section: Introductionmentioning

confidence: 99%

Mutation spectrum analysis of 29 causative genes in 43 Chinese patients with congenital hypothyroidism

et al. 2020

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congenital hypothyroidism (cH) is the most common neonatal endocrine disorder with a genetic origin. The purpose of the present study was to analyze the mutation spectrum of cH patients in china. a targeted next-generation sequencing panel covering all exons of 29 cH-related causative genes was used in 43 Han chinese patients with cH [11 dysgenesis and 32 glands in situ (GiS)]. The functional impact and pathogenicity of detected variants were analyzed using a comprehensive bioinformatics approach and co-segregation studies. a total of 47 rare non-polymorphic variants in 9 target genes associated with thyroid hormone synthesis (DUOX2, DUOXA2, TPO, TG, SLC26A4 and SLC5A5), thyroid stimulating hormone resistance (TSHR) and central hypothyroidism (PROP1 and TRHR) were identified in 31 patients (31/43, 72%). of these variants, 8 were novel, including 3 in DUOX2, 2 in TPO, 3 in TSHR and 1 in SLC5A5. Variants were mostly affected by DUOX2, TG, TPO and TSHR. approximately 44% of the patients (19/43) carried DUOX2 variants. The mutation detection rates in patients with GiS were higher compared with patients with dysgenesis [25/32 (78%) vs. 6/11 (54%)]. oligogenic mutations were detected in 25.6% of the total cases and 35% of the mutated cases. Genetic basis was ascertained in 13 patients, reaching a diagnosis detection rate of 30%. in conclusion, genetic defects in dyshormonogenesis, mainly in DUOX2, were the main genetic cause of cH in the chinese population. oligogenicity is highly involved in cH pathogenesis and may thus be an important factor in common phenotypic variability observed in patients with cH.

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Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2

Cited by 14 publications

References 13 publications

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

DUOX Defects and Their Roles in Congenital Hypothyroidism

Mutation spectrum analysis of 29 causative genes in 43 Chinese patients with congenital hypothyroidism

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