Identification and Functional Analysis of Novel Dual Oxidase 2 (DUOX2) Mutations in Children with Congenital or Subclinical Hypothyroidism

Marco, Giuseppina De; Agretti, Patrizia; Montanelli, Lucia; Cosmo, Caterina Di; Bagattini, Brunella; Servi, Melissa De; Ferrarini, Eleonora; Dimida, Antonio; Ferreira, Andrea Cláudia Freitas; Molinaro, Angelo; Ceccarelli, Claudia; Brozzi, Federica; Pinchera, Aldo; Vitti, Paolo; Tonacchera, Massimo

doi:10.1210/jc.2010-2467

Cited by 64 publications

(49 citation statements)

References 17 publications

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“…This was consistent with a previous expression study (25). Previous studies showed that p.H678R did not reduce H 2 O 2 production (14,34). The most prevalent variant detected in this study was p.H678R.…”

Section: Discussionsupporting

confidence: 93%

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: Discussionsupporting

confidence: 93%

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 crucial role of DUOX2 has been demonstrated in patients suffering from a partial iodide organification defect and CH caused by mutations in the Duox2 gene, whereas monoallelic inactivation of the Duox2 or Duoxa2 gene is typically associated with transient CH (14)(15)(16)(17)(18)(19). Abnormalities of H 2 O 2 generation and iodination of Tg may be related to the development of papillary carcinoma or Hashimoto's thyroiditis (51,52).…”

Section: Discussionmentioning

confidence: 99%

“…The major role played by DUOXs in thyroid hormone synthesis has been proved in patients suffering from congenital hypothyroidism (CH) that is caused by mutations of either DUOX2 or DUOXA2 (14)(15)(16)(17)(18)(19); while the roles of DUOX1 and DUOXA1 in the thyroid are still elusive. The DUOX proteins have two Ca 2 + binding EF-hand motifs that are considered as accounting for their Ca 2 + -dependent activity (20,21).…”

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confidence: 99%

Regulation of Dual Oxidase Expression and H₂O₂Production by Thyroglobulin

Yoshihara

Hara

Kawashima

et al. 2012

Thyroid

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Background: Thyroglobulin (Tg) is a macromolecular precursor in thyroid hormone synthesis to which iodine is stably bound. Tg, which is stored in the follicular space, is also a potent negative feedback regulator of follicular function, and this is achieved by suppressing mRNA levels of thyroid-specific genes such as the sodium/iodide symporter (Slc5a5), Tg, and thyroid peroxidase. Dual oxidase 1 (DUOX1) and DUOX2, originally identified in the thyroid, are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases that are necessary to produce the H 2 O 2 required for thyroid hormone biosynthesis. Since follicular Tg regulates the expression of genes that are essential for thyroid hormone synthesis, we hypothesized that Tg might also regulate DUOX expression and H 2 O 2 production. Methods: Rat thyroid FRTL-5 cells were treated with Tg, and the mRNA expression of Duox1 and Duox2 and their corresponding maturation factors Duoxa1 and Duoxa2 were evaluated by DNA microarray and real-time PCR. Duox2 promoter activity was examined by luciferase reporter gene assay. Protein levels of DUOX2 were also examined by Western blot analysis. Intracellular H 2 O 2 generation was quantified by a fluorescent dye, 5-(and-6)-chloromethyl-2¢,7¢-dichlorodihydrofluorescein diacetate, and acetyl ester (CM-H 2 DCFDA). Results: mRNA levels of Duox2 and its activation factor Duoxa2 (but not Duox1 or Duoxa1) were significantly suppressed by Tg in a dose-dependent manner and a time-dependent fashion in rat thyroid FRTL-5 cells. DUOX2 promoter activity was significantly suppressed by Tg in a dose-dependent manner. Protein levels of DUOX2 and H 2 O 2 generation in cells were also reduced by Tg treatment. Conclusions: We show that physiological concentrations of Tg suppressed the expression and function of DUOX2 in thyroid cells. These results suggest that Tg is a strong suppressor of the expression and the activity of DUOX2/DUOXA2, thereby regulating iodide organification and hormone synthesis in the thyroid. The evidence supports a reported model in which accumulated Tg in thyroid follicles plays important roles in autoregulating the function of individual follicles, which produces the basis of follicular heterogeneity.

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“…Dual oksidaz 2 (DUOX2) geninde missense mutasyon, fosfodiesteraz 8B gen mutasyonu, tiroid peroksidaz mutasyonları, TSH yükselmesine neden olarak SH kliniği oluş-turabilirler [24][25][26]. Doğumsal hastalıklarla da birliktelik gösterilmiştir [14].…”

Section: • Laboratuvar Hatasıunclassified

Insidious danger in childhood era's: subclinical hypothyroidism

2017

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Insidious danger in childhood era's; subclinical hypothyroidism erleme d Öz Tiroid hormonları; santral sinir sistemi gelişimi, büyüme, gelişme, vücut ısısı regülasyonu, lipit, karbonhidrat ve enerji metabolizması, iskelet sistemi üzerinde önemli role sahiptir. Diğer yönden çocukluk çağında santral sinir sistemi myelinizasyonunda görevli olduğu için önemi farklıdır. Subklinik hipotiroidi, serum tiroid stimulan hormon seviyesinin orta düzeyde artması ile birlikte serum tiroid hormon seviyelerinin normal referans laboratuvar aralı-ğında olmasıdır. Çocuklarda %2 oranında görülmektedir. Etiyolojisinin büyük bir kısmını otoimmün tiroidit ve iyot eksikliği oluşturmaktadır. Asemptomatik olguların zamanında tanımlanması ve tedavisi önemlidir. Olgularda guatr, büyüme-gelişme geriliği veya duraksaması, ders başarısında azalma, negativizm, depresyon, obezite, demir eksikliği anemisi, dislipidemi, kemik yaşı geriliğinde levotiroksin tedavisi başlanması uygundur. Anahtar sözcükler: Çocukluk çağı, subklinik hipotiroidizm AbstractThyroid hormones have an important role on the central nervous system, growth, development, body temperature regulation, metabolism of lipid, carbohydrate and energy, musculoskeletal system. The other hand, it has a different importance for its role in the myelinization of the central nervous system during the childhood period. Subclinical hypothyroidism (SH), is diagnosed when peripheral thyroid hormone levels are within normal reference laboratory range but serum thyroid-stimulating hormone levels are mildly elevated. Prevalance of subclinical hypothyroidism in chilhood is seen about %2. The majority of its etiology is due to the autoimmune thyroiditis and iodine deficiency. It is important to diagnose and treat the asymptomatic cases in a timely manner. Thyroxin treatment should be started if goiter, growth velocity is slowed down, decline in school success, negativism, depression, obesity, refractory iron deficiency anemia dyslipidemia, bone age retardation.

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Identification and Functional Analysis of Novel Dual Oxidase 2 (DUOX2) Mutations in Children with Congenital or Subclinical Hypothyroidism

Cited by 64 publications

References 17 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

Regulation of Dual Oxidase Expression and H₂O₂Production by Thyroglobulin

Insidious danger in childhood era's: subclinical hypothyroidism

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Identification and Functional Analysis of Novel Dual Oxidase 2 (DUOX2) Mutations in Children with Congenital or Subclinical Hypothyroidism

Cited by 64 publications

References 17 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

Regulation of Dual Oxidase Expression and H2O2Production by Thyroglobulin

Insidious danger in childhood era's: subclinical hypothyroidism

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Regulation of Dual Oxidase Expression and H₂O₂Production by Thyroglobulin