Congenital hypothyroidism caused by a mutation in the Na+/l− symporter

Fujiwara, Hirokazu; Tatsumi, Ke-ita; Miki, Kazunori; Harada, Tokuzo; Miyai, Kiyoshi; Takai, Shin‐ichiro; Amino, Nobuyuki

doi:10.1038/ng0697-124

Cited by 143 publications

(104 citation statements)

References 9 publications

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“…Em crianças, a tireóide, inicialmente, pode se apresentar com tamanho normal e aumentar com o transcorrer do tempo. Em nível molecular, mutações inativadoras homozigóticas puderam ser identificadas como responsáveis pela captação comprometida de iodeto em alguns indivíduos (29,30). Em nosso meio estudamos um paciente adulto com volumoso bócio e hipotireoidismo, apresentando captação de radioiodo ao redor de 1%, na presença de TSH elevado.…”

Section: Disormonogênese Tireóideaunclassified

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Rubio¹,

Knobel²,

Nascimento³

et al. 2002

Arq Bras Endocrinol Metab

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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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Section: Disormonogênese Tireóideaunclassified

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Rubio¹,

Knobel²,

Nascimento³

et al. 2002

Arq Bras Endocrinol Metab

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“…The resulting impairment in I − uptake in the thyroid leads to congenital hypothyroidism, which, unless treated early in life by TH administration, causes goiter and even mental retardation. Study of the 14 ITD-causing NIS mutations identified to date (27)(28)(29)(30)(31)(32)(33)(34)(35)(36) has been instrumental in the identification of residues key for NIS transport activity (5, 16, 17, 22-25, 37, 38). For example, the analysis of T354P revealed the role in NIS function of TMS9, where this mutation is located (23).…”

Section: Significancementioning

confidence: 99%

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Ferrandino

Nicola

Sánchez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The sodium/iodide symporter (NIS) mediates active I− transport in the thyroid—the first step in thyroid hormone biosynthesis—with a 2 Na+: 1 I− stoichiometry. The two Na+ binding sites (Na1 and Na2) and the I− binding site interact allosterically: when Na+ binds to a Na+ site, the affinity of NIS for the other Na+ and for I− increases significantly. In all Na+-dependent transporters with the same fold as NIS, the side chains of two residues, S353 and T354 (NIS numbering), were identified as the Na+ ligands at Na2. To understand the cooperativity between the substrates, we investigated the coordination at the Na2 site. We determined that four other residues—S66, D191, Q194, and Q263—are also involved in Na+ coordination at this site. Experiments in whole cells demonstrated that these four residues participate in transport by NIS: mutations at these positions result in proteins that, although expressed at the plasma membrane, transport little or no I−. These residues are conserved throughout the entire SLC5 family, to which NIS belongs, suggesting that they serve a similar function in the other transporters. Our findings also suggest that the increase in affinity that each site displays when an ion binds to another site may result from changes in the dynamics of the transporter. These mechanistic insights deepen our understanding not only of NIS but also of other transporters, including many that, like NIS, are of great medical relevance.

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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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Congenital hypothyroidism caused by a mutation in the Na+/l− symporter

Cited by 143 publications

References 9 publications

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

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

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Congenital hypothyroidism caused by a mutation in the Na+/l− symporter

Cited by 143 publications

References 9 publications

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Hipotireoidismo Congênito: Recentes Avanços em Genética Molecular

Na + coordination at the Na2 site of the Na + /I − symporter

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

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Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter