Thyroid dysgenesis caused by PAX8 mutation: The hypermutability with CpG dinucleotides at codon 31

Komatsu, Masaki; Takahashi, Tsutomu; Takahashi, Ikuko; Nakamura, Masaaki; Takahashi, Ikuo; Takada, Goro

doi:10.1067/mpd.2001.117071

Cited by 59 publications

(53 citation statements)

References 7 publications

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“…This mutation is located in a highly conserved area of the gene, which encodes the DNA-binding domain of the PAX8 protein. Other mutations in this area of the gene have been described before and have been characterized at the molecular level (4,5,7,(9)(10)(11)(12)(13)(14)(15)17). In agreement with previously reported mutations (R31C, R31H, Q40P, R52P, S54G, H55Q, C57Y, L62R), S54R has lost its ability to bind to TPO promoter-binding sites.…”

Section: Discussionsupporting

confidence: 69%

“…Furthermore, PAX8 and TTF1 synergistically activate the promoter of human TG (3). So far, 13 different mutations in the PAX8 gene have been reported (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and the phenotypes of affected individuals vary considerably. Even within the same family, heterozygous individuals with PAX8 mutations can have no thyroid gland abnormality, have thyroid hypoplasia or TD (6), making it very difficult to identify individuals harboring a PAX8 gene mutation (1).…”

Section: Introductionmentioning

confidence: 99%

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Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA Binding Region: In vitro studies reveal different pathogenic mechanisms.

Hermanns¹,

Grasberger²,

Cohen³

et al. 2012

Thyroid

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Background: Mutations in PAX8, a transcription factor gene, cause thyroid dysgenesis (TD). The extreme variability of the thyroid phenotype makes it difficult to identify individuals harboring PAX8 gene mutations. Here we describe two patients with TD and report two novel PAX8 gene mutations (S54R and R133Q). We performed in vitro studies to functionally characterize these mutations. Methods: Using PAX8 expression vectors, we investigated whether the PAX8 mutants localized correctly to the nucleus. To analyze the DNA-binding properties of S54R and R133Q, electrophoretic mobility shift assays were performed. Furthermore, we measured whether the mutant PAX8 proteins were able to activate the thyroglobulin (TG)-and the thyroperoxidase (TPO)-promoters. Results: S54R had an impaired binding to DNA and a negligible activity on the TG-and the TPO-promoters. The DNA-binding property of R133Q, which is located in the highly conserved terminal portion of the PAX8 DNA-binding domain, was normal. Interestingly, it also exhibited dramatically impaired activation of the TGand TPO-promoters. However, R133Q has no dominant negative effect on the WT protein in vitro. Thus, the underlying molecular mechanism by which the function of R133Q is impaired remains to be elucidated. Conclusions: We identified and functionally characterized two novel mutations of the PAX8 gene that lead to TD by distinct mechanisms. A structural defect of the mutant R133Q leading to a reduced capability for induced fit upon DNA interaction might explain the disparity between its apparently normal binding to DNA, but lack of promoter activation.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA Binding Region: In vitro studies reveal different pathogenic mechanisms.

Hermanns¹,

Grasberger²,

Cohen³

et al. 2012

Thyroid

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“…To date, 15 mutations have been identified in 5 exons of PAX8 (1,(13)(14)(15)(16)(17)(18)(19)(20)(21). The exon number 3 and 4 which make the paired box domain are the hotspot with 9 mutations recognized.…”

mentioning

confidence: 99%

“…Exon 7 with 3 and exon 9 and 12, each with 1 mutation recognized. In Italy 8 mutations out of 14 have been found (1,13,17,18,(20)(21), 3 in French (13,(15)(16)(18)(19) and 1 in each Japanese (15), German (19) and American patients with thyroid dysgenesis (14).…”

mentioning

confidence: 99%

Mutations in the gene encoding paired box domain (PAX8) are not a frequent cause of congenital hypothyroidism (CH) in Iranian patients with thyroid dysgenesis

Mahjoubi

Mohammadi

Montazeri

et al. 2010

Arq Bras Endocrinol Metab

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Objective: Congenital hypothyroidism (CH) may be caused by defects in the thyroid or in one of the stages in the synthesis of thyroid hormones. Thyroid dysgenesis may be associated with mutation in the paired box transcription factor 8 (PAX8) gene. We attempted to screen PAX8 gene mutation in 50 CH patients with thyroid dysgenesis. Subjects and methods: The patients were classified in two groups as agenesis and ectopic based on biochemical and para clinical tests. By employing PCR, Single Strand Conformation Polymorphism (SSCP) and sequencing, exons 3 to 12 of PAX8 gene with their exon-intron boundaries were studied. Results: No mutation was found in these patients in any of the exons. Conclusion: Our results, once again, indicate that the PAX8 mutation rate is very low and can only explain a minority of the cases. Therefore, it is highly needed to further investigate the genes controlling development and function of thyroid. Arq Bras Endocrinol Metab. 2010;54(6):555-9 Keywords Congenital hypothyroidism; thyroid dysgenesis; PAX8; gene mutation ReSumo Objetivo: O hipotireoidismo congênito (HC) pode ser causado por defeitos na formação da tireoide ou em uma das etapas da síntese dos hormônios tireoidianos. A disgenesia da tireoide pode ser associada a mutações no fator de transcrição PAX8. Neste estudo, foram rastreadas mutações no gene PAX8 em 50 pacientes com CH com disgenesia da tireoide. Sujeitos e méto-dos: Os pacientes foram classificados em dois grupos, com agenesia ou com ectopia, segundo os testes bioquímicos e paraclínicos. Foram empregadas as técnicas de SSCP (Single Strand Conformation Polymorphism) e sequenciamento para analisar os éxons 3 a 12 do gene PAX8 e suas bordas éxon-intron. Resultados: Nenhuma mutação foi encontrada nesses pacientes, em qualquer um dos éxons. Conclusão: Nossos resultados, mais uma vez, indicam que a taxa de mutação PAX8 é muito baixa e só pode explicar a minoria dos casos. Portanto, é altamente necessário investigar outros genes que controlam o desenvolvimento e as funções tireoideanas.Arq Bras Endocrinol Metab. 2010;54(6):555-9 Descritores Hipotireoidismo congênito; disgenesia da tireoide; PAX8; mutação genética

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“…Dez mutações do gene PAX8 (oito missense, uma nonsense e uma deleção) já foram descritas em casos esporádicos e familiares com transmissão autossômica dominante de HC com DT, todas em heterozigose (Tabela 2) (40)(41)(42)(43)(44)(45)(46)(47)(48). O fenótipo tiroidiano é bastante variável (de casos leves àqueles com hipoplasia grave) entre indivíduos afetados da mesma família, o que indica penetrân-cia incompleta (41,45).…”

Section: Pax8unclassified

Novos aspectos da genética e dos mecanismos moleculares da morfogênese da tiróide para o entendimento da disgenesia tiroidiana

Ramos

Nesi-França

Maciel

2008

Arq Bras Endocrinol Metab

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A organogênese da tiróide ainda não está completamente elucidada, assim como também não se conhece o mecanismo patogenético da maioria dos casos de disgenesias tiroidianas. Vários genes têm sido identifi cados como importantes para a sobrevivência, a proliferação e a migração dos precursores das células tiroidianas e tem-se demonstrado que eles atuam de modo integrado. Além disso, por meio da geração de camundongos geneticamente modifi cados, diversos estudos têm trazido melhor entendimento para o papel destes genes na morfogênese tiroidiana. Finalmente, tem-se também evidenciado que mutações em alguns destes genes são responsáveis pelo desenvolvimento de disgenesias tiroidianas em crianças com hipotiroidismo congênito. O objetivo desta revisão é sumarizar os aspectos moleculares do desenvolvimento tiroidiano, descrever os modelos animais e respectivos fenótipos e oferecer novas informações sobre a ontogenia e a patogênese das disgenesias tiroidianas humanas. ABSTRACT New Aspects of Genetics and Molecular Mechanisms on Thyroid Morphogenesis for the Understading of Thyroid Dysgenesia.The elucidation of the molecular mechanisms underlying the very early steps of thyroid organogenesis and the etiology of most cases of thyroid dysgenesis are poorly understood. Many genes have been identifi ed as important contributors to survival, proliferation and migration of thyroid cells precursors, acting as an integrated and complex regulatory network. Moreover, by generation of mouse mutants, the studies have provided better knowledge of the role of these genes in the thyroid morphogenesis. In addition, it is likely that a subset of patients has thyroid dysgenesis as a result of mutations in regulatory genes expressed during embryogenesis. This review summarizes molecular aspects of thyroid development, describes the animal models and phenotypes known to date and provides information about novel insights into the ontogeny and pathogenesis of human thyroid dysgenesis.

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Thyroid dysgenesis caused by PAX8 mutation: The hypermutability with CpG dinucleotides at codon 31

Cited by 59 publications

References 7 publications

Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA Binding Region: In vitro studies reveal different pathogenic mechanisms.

Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA Binding Region: In vitro studies reveal different pathogenic mechanisms.

Mutations in the gene encoding paired box domain (PAX8) are not a frequent cause of congenital hypothyroidism (CH) in Iranian patients with thyroid dysgenesis

Novos aspectos da genética e dos mecanismos moleculares da morfogênese da tiróide para o entendimento da disgenesia tiroidiana

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