Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter.

RESUMOO hipotireoidismo congênito (HC), detectado em recém-nascidos rastreados ao nascer, é causado por anomalias na organogênese (agenesia, tireóide ectópica, hipoplasia tireóidea) ou por defeitos específicos na hormonogênese. Mais raramente, o hipotireoidismo congênito tem origem em defeitos genéticos centrais, localizados no eixo hipotálamo-hipófise ou em mutações do gene do TSH-beta ou no receptor de TSH. Defeitos específicos da hormonogênese são causados por mutações no gene codificador para a proteína transportadora de iodeto (NIS), no gene da peroxidase (TPO), no gene traduzindo a pendrina (síndrome de Pendred), no gene da tireoglobulina, além de mutações que afetam o receptor de hormônio tireóideo (resistência genética ao HT) ou aos vários defeitos no transporte de HT na circulação periférica. Na maioria dos casos, os defeitos genéticos indicados criam condições para fenótipo com bócio e grau variável de hipotireoidismo, podendo a mutação genética ter expressão variável durante a vida adulta. Congenital hypothyroidism (CH), as seen in the neonatal period, is predominantly caused by defects in the organogenesis (athyreosis, ectopic thyroid, thyroid hypoplasia) or by specific defects in hormonogenesis (dyshormonogenesis). Central hypothyroidism is rare, being linked to specific transcription factors involved in the maturation of the hypothalamic-pituitary axis or by mutations in the TSH-beta gene. Dyshormonogenesis may be caused by mutation coding for thyroid proteins such as the TSH receptor, the sodium-iodide symporter (NIS), the pendrin (Pendred's syndrome), thyroid peroxidase (TPO), thyroglobulin (Tg), thyroid dehalogenase, the receptor for thyroid hormone (TR-beta) or thyroid transport proteins (TBG, transthyretin). Usually, most of these defective genes will induce a phenotype with goiter and variable degree of hypothyroidism that may be present in the neonatal period or will gradually develop during post-natal life. Moreover, the genetic expression may be partial or total according to the specific mutation occurring in the involved genes.

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“…Têm sido registradas na literatura, mutações no gene da TPO em várias famílias onde o defeito ocorre de forma parcial ou total (45)(46)(47)(48).…”

Section: Tireoperoxidaseunclassified

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Rubio¹,

Knobel²,

Nascimento³

et al. 2002

Arq Bras Endocrinol Metab

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“…TPO is also a major autoantigen in the pathogenesis of autoimmune thyroid diseases (4 -6). Also, defective TPO causes congenital hypothyroidism because of an iodide organification defect linked with mutations of the TPO gene (7)(8)(9).…”

Section: Thyroid Peroxidase (Tpo)mentioning

confidence: 99%

Human Thyroperoxidase in Its Alternatively Spliced Form (TPO2) Is Enzymatically Inactive and Exhibits Changes in Intracellular Processing and Trafficking

Niccoli¹,

Fayadat²,

Panneels³

et al. 1997

Journal of Biological Chemistry

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Thyroid peroxidase (TPO1) is a membrane-bound heme-containing glycoprotein that catalyzes the synthesis of thyroid hormones. We generated stable cell lines expressing TPO1 and the alternatively spliced isoform TPO2. Pulse-chase studies showed that TPO2 half-life was dramatically decreased as compared with TPO1. The sensitivity of TPO2 to endo-␤-N-acetylglucosaminidase H indicated that the protein is processed through the endoplasmic reticulum and bears high mannosetype structures. Cell surface biotinylation experiments showed that the two isoforms also differ in their intracellular trafficking. TPO2 was totally retained in the cell, whereas 15% of TPO1 reached the cell surface. The inability of TPO2 to come out of the intracellular compartments was related to structural changes in the molecule. Evidence of these changes was obtained through the lack of recognition of TPO2 by half of the 13 TPO monoclonal antibodies tested in immunoprecipitation experiments. Our data suggest that because of an improper folding, TPO2 is trapped in the endoplasmic reticulum and rapidly degraded. The failure of incorporation of [ 14 C]aminolevulinic acid in the cultured cells showed that TPO2 did not bind to heme, whereas TPO1 did. This result was confirmed through a guaiacol assay showing that TPO2 is enzymatically inactive.

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“…Introduction sodium iodide symporter (NIS), pendrin (PDS), dual oxidase 2 (DUOX2), dual oxidase maturation factor 2 (DUOXA2), dual oxidase 1 (DUOX1), dual oxidase 1 maturation factor (DUOXA1), and iodotyrosine deiodinase (IYD) (4,5,6,7,8,9,10,11,12), and mutations have been detected in numerous undiagnosed cases. Recent reports have shown that a high proportion of CH cases are caused by mutations in hormone-producing enzymes, and DUOX2 mutations are one of the most frequent causes (13,14,15,16).…”

mentioning

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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Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter.

Cited by 170 publications

References 21 publications

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Human Thyroperoxidase in Its Alternatively Spliced Form (TPO2) Is Enzymatically Inactive and Exhibits Changes in Intracellular Processing and Trafficking

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

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