Congenital hypothyroidism caused by a novel mutation of the dual oxidase 2 (DUOX2) gene

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

doi:10.1515/jpem-2012-0082

Cited by 23 publications

(14 citation statements)

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“…This recent study also suggested the involvement of a monoallelic variant of DUOX2 in the development of transient CH. Other reports have shown that biallelic DUOX2 mutations cause mild to moderate CH (13,14,15,16,19,22,30). Recently, some studies have shown that DUOX2 defects are the predominant cause of CH associated with dyshormonogenesis (13,14,15,16,25,26).…”

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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“…Furthermore, the authors established the first genetic cause for transient CH with mono-allelic inactivation of DUOX2 and postulated that DUOX2 biallelic mutations would be associated with a permanent form of CH. However, numerous subsequent studies provide further evidence that the permanent or transient nature of congenital hypothyroidism is not directly related to the number of inactivated DUOX2 alleles, suggesting the existence of other pathophysiological factors [95][96][97][98].…”

Section: Duox Defects In Congenital Hypothyroidismmentioning

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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“…Eleven known causative genes of primary CH ( DUOXA2 , DUOX2 , FOXE1 , IYD , NKX2-1 , PAX8 , SLC5A5, SLC26A4, TG , TPO , and TSHR ) and 2 candidate genes ( DUOX1 and DUOXA1 ) were analyzed using a next-generation sequencer MiSeq (Illumina Inc., San Diego, CA, USA) following the protocol of SureSelect (Agilent Technologies, Santa Clara, CA, USA) as described previously [22]. Presences of mutations called by next-generation sequencing were confirmed by conventional PCR-based Sanger sequencing.…”

Section: Case Reportmentioning

confidence: 99%

Fetal Goitrous Hypothyroidism and Polyhydramnios in a Patient with Compound Heterozygous <b><i>DUOXA2</i></b> Mutations

et al. 2018

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Background: Fetal goiter is only rarely observed in pregnant women without autoimmune thyroid disorders, and there is no epidemiological data on its pathophysiology. Dual oxidase maturation factor 2 (DUOXA2), together with dual oxidase 2, serves pivotal roles in thyroid hormone biosynthesis. To date, all reported patients with DUOXA2 mutations were diagnosed postnatally through newborn screening for congenital hypothyroidism. Case Report: The mother of a male fetus presented at 33 + 4 gestational weeks (GW) with a fetal goiter and polyhydramnios. Cordocentesis revealed fetal hypothyroidism (TSH 253.4 mU/L, FT₄ 0.29 ng/dL). Intra-amniotic levothyroxine injections were performed at GW 34 + 3 and 35 + 3. The patient was born after spontaneous vaginal delivery at 35 + 6 GW without obstetrical complications. He was treated with levothyroxine until the age of 6 years when reevaluation of his thyroid functions showed normal results (TSH 1.32 mU/L, FT₄ 1.81 ng/dL). Eleven causative genes of CH, including DUOXA2, were analyzed with use of a next-generation sequencing technique. Results: A next-generation sequencing-based mutation screen led us to find that he was compound heterozygous for 2 previously reported nonsense DUOXA2 mutations (p.[Tyr138*];[Tyr246*]). Conclusion: The present case not only illustrates the phenotypic diversity of DUOXA2 mutation carriers but also implies that DUOXA2 is important in prenatal thyroid hormone production.

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Congenital hypothyroidism caused by a novel mutation of the dual oxidase 2 (DUOX2) gene

Cited by 23 publications

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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

Fetal Goitrous Hypothyroidism and Polyhydramnios in a Patient with Compound Heterozygous <b><i>DUOXA2</i></b> Mutations

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