Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid gl...

Autores
Esperante, Sebastian; Rivolta, Carina Marcela; Miravalle, Lucrecia; Herzovich, Viviana; Iorcansky, Sonia; Baralle, Marco; Targovnik, Hector Manuel
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Context: Thyroid dysgenesis may be associated with mutations in the paired box transcription factor 8 (PAX8) gene and is characterized by congenital hypothyroidism transmitted in an autosomal dominant mode. Objectives: The aim of this study was to identify new mutations in the PAX8 gene. Sixty congenital hypothyroidism-affected individuals with dysgenetic (agenesis, ectopia and hypoplasia) and eutopic thyroid glands were studied. Methods: The 12 exons of the PAX8 gene along with their exon-intron boundaries were amplified from genomic DNA and a mutational screening was performed by single-strand conformational polymorphism (SSCP) followed by direct sequencing of samples with abnormal migration patterns. The PAX8 mutations were functionally characterized by transient transfection experiments. Results: Molecular analysis of the PAX8 gene indicated that four affected individuals had four sequence differences: three novel variations [c.699C>T (p.L233L), c.1006G>A (p.G336S) and c.1317A>G (p.A439A)] and one recently reported [c.674C>T (p.T225M)], whereas the 56 remaining patients showed only wild-type alleles of PAX8. p.T225M, p.L233L and p.G336S variants were not detected in 530 chromosomes from 265 subjects randomly selected from the general population, whereas the p.A439A variant was identified in only one of the 530 chromosomes analysed. Functional analysis of the nonsynonymous substitutions showed that the p.T225M and p.G336S proteins had not lost their ability to bind a specific DNA sequence and to activate the transcription of the thyroglobulin (TG) promoter in synergy with thyroid transcription factor 1 (TTF1). Conclusions: We report the occurrence of two nonsynonymous substitutions, one recently reported (p.T225M) and one novel (p.G336S), and two novel synonymous substitutions (p.L233L and p.A439A) in the PAX8 gene. p.T225M and p.G336S are rare sequence variants or may act by inhibiting an unknown particular function. Our study also confirms the very low prevalence of PAX8 mutations in thyroid dysgenesis.
Fil: Esperante, Sebastian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rivolta, Carina Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina
Fil: Miravalle, Lucrecia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina
Fil: Herzovich, Viviana. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina
Fil: Iorcansky, Sonia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina
Fil: Baralle, Marco. International Centre For Genetic Engineering And Biotechnology.; Italia. Instituto Cent.for Genetic Engineering ; Italia
Fil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina
Materia
Congenital Hypothyroidism
Dysembriogenesis
Thyroid Dysgenesis
Pax8 Gene
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/36736
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/36736
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glandsEsperante, SebastianRivolta, Carina MarcelaMiravalle, LucreciaHerzovich, VivianaIorcansky, SoniaBaralle, MarcoTargovnik, Hector ManuelCongenital HypothyroidismDysembriogenesisThyroid DysgenesisPax8 Genehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Context: Thyroid dysgenesis may be associated with mutations in the paired box transcription factor 8 (PAX8) gene and is characterized by congenital hypothyroidism transmitted in an autosomal dominant mode. Objectives: The aim of this study was to identify new mutations in the PAX8 gene. Sixty congenital hypothyroidism-affected individuals with dysgenetic (agenesis, ectopia and hypoplasia) and eutopic thyroid glands were studied. Methods: The 12 exons of the PAX8 gene along with their exon-intron boundaries were amplified from genomic DNA and a mutational screening was performed by single-strand conformational polymorphism (SSCP) followed by direct sequencing of samples with abnormal migration patterns. The PAX8 mutations were functionally characterized by transient transfection experiments. Results: Molecular analysis of the PAX8 gene indicated that four affected individuals had four sequence differences: three novel variations [c.699C>T (p.L233L), c.1006G>A (p.G336S) and c.1317A>G (p.A439A)] and one recently reported [c.674C>T (p.T225M)], whereas the 56 remaining patients showed only wild-type alleles of PAX8. p.T225M, p.L233L and p.G336S variants were not detected in 530 chromosomes from 265 subjects randomly selected from the general population, whereas the p.A439A variant was identified in only one of the 530 chromosomes analysed. Functional analysis of the nonsynonymous substitutions showed that the p.T225M and p.G336S proteins had not lost their ability to bind a specific DNA sequence and to activate the transcription of the thyroglobulin (TG) promoter in synergy with thyroid transcription factor 1 (TTF1). Conclusions: We report the occurrence of two nonsynonymous substitutions, one recently reported (p.T225M) and one novel (p.G336S), and two novel synonymous substitutions (p.L233L and p.A439A) in the PAX8 gene. p.T225M and p.G336S are rare sequence variants or may act by inhibiting an unknown particular function. Our study also confirms the very low prevalence of PAX8 mutations in thyroid dysgenesis.Fil: Esperante, Sebastian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rivolta, Carina Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Miravalle, Lucrecia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; ArgentinaFil: Herzovich, Viviana. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; ArgentinaFil: Iorcansky, Sonia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; ArgentinaFil: Baralle, Marco. International Centre For Genetic Engineering And Biotechnology.; Italia. Instituto Cent.for Genetic Engineering ; ItaliaFil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaWiley Blackwell Publishing, Inc2008-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/36736Esperante, Sebastian; Rivolta, Carina Marcela; Miravalle, Lucrecia; Herzovich, Viviana; Iorcansky, Sonia; et al.; Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands; Wiley Blackwell Publishing, Inc; Clinical Endocrinology; 68; 5; 5-2008; 828-8350300-0664CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1111/j.1365-2265.2007.03111.xinfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2007.03111.x/abstractinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:38:43Zoai:ri.conicet.gov.ar:11336/36736instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:38:43.339CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands
title Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands
spellingShingle Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands
Esperante, Sebastian
Congenital Hypothyroidism
Dysembriogenesis
Thyroid Dysgenesis
Pax8 Gene
title_short Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands
title_full Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands
title_fullStr Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands
title_full_unstemmed Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands
title_sort Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands
dc.creator.none.fl_str_mv Esperante, Sebastian
Rivolta, Carina Marcela
Miravalle, Lucrecia
Herzovich, Viviana
Iorcansky, Sonia
Baralle, Marco
Targovnik, Hector Manuel
author Esperante, Sebastian
author_facet Esperante, Sebastian
Rivolta, Carina Marcela
Miravalle, Lucrecia
Herzovich, Viviana
Iorcansky, Sonia
Baralle, Marco
Targovnik, Hector Manuel
author_role author
author2 Rivolta, Carina Marcela
Miravalle, Lucrecia
Herzovich, Viviana
Iorcansky, Sonia
Baralle, Marco
Targovnik, Hector Manuel
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Congenital Hypothyroidism
Dysembriogenesis
Thyroid Dysgenesis
Pax8 Gene
topic Congenital Hypothyroidism
Dysembriogenesis
Thyroid Dysgenesis
Pax8 Gene
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Context: Thyroid dysgenesis may be associated with mutations in the paired box transcription factor 8 (PAX8) gene and is characterized by congenital hypothyroidism transmitted in an autosomal dominant mode. Objectives: The aim of this study was to identify new mutations in the PAX8 gene. Sixty congenital hypothyroidism-affected individuals with dysgenetic (agenesis, ectopia and hypoplasia) and eutopic thyroid glands were studied. Methods: The 12 exons of the PAX8 gene along with their exon-intron boundaries were amplified from genomic DNA and a mutational screening was performed by single-strand conformational polymorphism (SSCP) followed by direct sequencing of samples with abnormal migration patterns. The PAX8 mutations were functionally characterized by transient transfection experiments. Results: Molecular analysis of the PAX8 gene indicated that four affected individuals had four sequence differences: three novel variations [c.699C>T (p.L233L), c.1006G>A (p.G336S) and c.1317A>G (p.A439A)] and one recently reported [c.674C>T (p.T225M)], whereas the 56 remaining patients showed only wild-type alleles of PAX8. p.T225M, p.L233L and p.G336S variants were not detected in 530 chromosomes from 265 subjects randomly selected from the general population, whereas the p.A439A variant was identified in only one of the 530 chromosomes analysed. Functional analysis of the nonsynonymous substitutions showed that the p.T225M and p.G336S proteins had not lost their ability to bind a specific DNA sequence and to activate the transcription of the thyroglobulin (TG) promoter in synergy with thyroid transcription factor 1 (TTF1). Conclusions: We report the occurrence of two nonsynonymous substitutions, one recently reported (p.T225M) and one novel (p.G336S), and two novel synonymous substitutions (p.L233L and p.A439A) in the PAX8 gene. p.T225M and p.G336S are rare sequence variants or may act by inhibiting an unknown particular function. Our study also confirms the very low prevalence of PAX8 mutations in thyroid dysgenesis.
Fil: Esperante, Sebastian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rivolta, Carina Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina
Fil: Miravalle, Lucrecia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina
Fil: Herzovich, Viviana. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina
Fil: Iorcansky, Sonia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina
Fil: Baralle, Marco. International Centre For Genetic Engineering And Biotechnology.; Italia. Instituto Cent.for Genetic Engineering ; Italia
Fil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina
description Context: Thyroid dysgenesis may be associated with mutations in the paired box transcription factor 8 (PAX8) gene and is characterized by congenital hypothyroidism transmitted in an autosomal dominant mode. Objectives: The aim of this study was to identify new mutations in the PAX8 gene. Sixty congenital hypothyroidism-affected individuals with dysgenetic (agenesis, ectopia and hypoplasia) and eutopic thyroid glands were studied. Methods: The 12 exons of the PAX8 gene along with their exon-intron boundaries were amplified from genomic DNA and a mutational screening was performed by single-strand conformational polymorphism (SSCP) followed by direct sequencing of samples with abnormal migration patterns. The PAX8 mutations were functionally characterized by transient transfection experiments. Results: Molecular analysis of the PAX8 gene indicated that four affected individuals had four sequence differences: three novel variations [c.699C>T (p.L233L), c.1006G>A (p.G336S) and c.1317A>G (p.A439A)] and one recently reported [c.674C>T (p.T225M)], whereas the 56 remaining patients showed only wild-type alleles of PAX8. p.T225M, p.L233L and p.G336S variants were not detected in 530 chromosomes from 265 subjects randomly selected from the general population, whereas the p.A439A variant was identified in only one of the 530 chromosomes analysed. Functional analysis of the nonsynonymous substitutions showed that the p.T225M and p.G336S proteins had not lost their ability to bind a specific DNA sequence and to activate the transcription of the thyroglobulin (TG) promoter in synergy with thyroid transcription factor 1 (TTF1). Conclusions: We report the occurrence of two nonsynonymous substitutions, one recently reported (p.T225M) and one novel (p.G336S), and two novel synonymous substitutions (p.L233L and p.A439A) in the PAX8 gene. p.T225M and p.G336S are rare sequence variants or may act by inhibiting an unknown particular function. Our study also confirms the very low prevalence of PAX8 mutations in thyroid dysgenesis.
publishDate 2008
dc.date.none.fl_str_mv 2008-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/36736
Esperante, Sebastian; Rivolta, Carina Marcela; Miravalle, Lucrecia; Herzovich, Viviana; Iorcansky, Sonia; et al.; Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands; Wiley Blackwell Publishing, Inc; Clinical Endocrinology; 68; 5; 5-2008; 828-835
0300-0664
CONICET Digital
CONICET
url http://hdl.handle.net/11336/36736
identifier_str_mv Esperante, Sebastian; Rivolta, Carina Marcela; Miravalle, Lucrecia; Herzovich, Viviana; Iorcansky, Sonia; et al.; Identification and characterization of four PAX8 rare sequence variants (p.T225M, p.L233L, p.G336S and p.A439A) in patients with congenital hypothyroidism and dysgenetic thyroid glands; Wiley Blackwell Publishing, Inc; Clinical Endocrinology; 68; 5; 5-2008; 828-835
0300-0664
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
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application/pdf
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dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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