New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter

Autores
Peteiro Gonzalez, D.; Lee, J.; Rodriguez Fontan, J.; Castro Piedras, I.; Cameselle Teijeiro, J.; Beiras, A.; Bravo, S. B.; Alvarez, C. V.; Hardy, D. M.; Targovnik, Hector Manuel; Arvan, P.; Lado Abeal, Joaquin
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Context: Thyroglobulin (TG) gene mutations cause congenital hypothyroidism (CH) with goiter. A founder effect has been proposed for some frequent mutations. Mutated proteins have a defect in intracellular transport causing intracellular retention with ultrastructural changes that resemble an endoplasmic reticulum storage disease. Objective: To reveal new aspects of thyroglobulin pathophysiology through clinical, cellular, molecular, and genetic studies in a family presenting with CH due to TG mutations from Galicia, an iodine-deficient area of Spain. Design: The included clinical evaluation of family members, DNA sequencing for TG gene mutation and haplotyping analysis, ultrastructural analysis of thyroid tissue specimens from affected subjects, analysis of effects of mutations found on TG gene transcription, and in vitro studies of cellular production and secretion of mutated proteins. Setting: Locations included primary care and university hospitals. Results: Family members with CH, mental retardation, and goiter were compound heterozygous for c.886C→T (p.R277X) and g.IVS35+1delG. For c.886C→T, a founder effect cannot be excluded, and its transcription was hardly detectable. g.IVS35+1delG caused an in-frame deletion in exon 35 and produced a protein that, although synthesized, could not be secreted. Ultrastructural analyses showed morphological changes consistent with an endoplasmic reticulum storage disease. Conclusion: The shorter thyroglobulin resulting from the novel g.IVS35+1delG was retained within the endoplasmic reticulum of thyrocytes,andtogether with p.R227X caused severe hypothyroidism with goiter. p.R277X, the most commonly described TG mutation, is caused by a TG exon-7 highly mutation-prone region, and the possibility thatsomecases were introduced to South America from Galicia cannot be excluded.
Fil: Peteiro Gonzalez, D.. Universidad de Santiago de Compostela; España
Fil: Lee, J.. Universidad de Santiago de Compostela; España
Fil: Rodriguez Fontan, J.. University of Michigan; Estados Unidos
Fil: Castro Piedras, I.. Universidad de Santiago de Compostela; España. Texas Tech University; Estados Unidos
Fil: Cameselle Teijeiro, J.. Universidad de Santiago de Compostela; España
Fil: Beiras, A.. Universidad de Santiago de Compostela; España
Fil: Bravo, S. B.. Universidad de Santiago de Compostela; España
Fil: Alvarez, C. V.. Universidad de Santiago de Compostela; España
Fil: Hardy, D. M.. Texas Tech University; Estados Unidos
Fil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina
Fil: Arvan, P.. Universidad de Santiago de Compostela; España. University of Michigan; Estados Unidos
Fil: Lado Abeal, Joaquin. Universidad de Santiago de Compostela; España. Texas Tech University; Estados Unidos
Materia
Congenital Goiter
Hypothyroidism
Thyroglobulin
Mutation
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:11336/67719
Acceder
id CONICETDig_296a797b2adc149edd937ab260760cc1
oai_identifier_str oai:ri.conicet.gov.ar:11336/67719
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital GoiterPeteiro Gonzalez, D.Lee, J.Rodriguez Fontan, J.Castro Piedras, I.Cameselle Teijeiro, J.Beiras, A.Bravo, S. B.Alvarez, C. V.Hardy, D. M.Targovnik, Hector ManuelArvan, P.Lado Abeal, JoaquinCongenital GoiterHypothyroidismThyroglobulinMutationhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Context: Thyroglobulin (TG) gene mutations cause congenital hypothyroidism (CH) with goiter. A founder effect has been proposed for some frequent mutations. Mutated proteins have a defect in intracellular transport causing intracellular retention with ultrastructural changes that resemble an endoplasmic reticulum storage disease. Objective: To reveal new aspects of thyroglobulin pathophysiology through clinical, cellular, molecular, and genetic studies in a family presenting with CH due to TG mutations from Galicia, an iodine-deficient area of Spain. Design: The included clinical evaluation of family members, DNA sequencing for TG gene mutation and haplotyping analysis, ultrastructural analysis of thyroid tissue specimens from affected subjects, analysis of effects of mutations found on TG gene transcription, and in vitro studies of cellular production and secretion of mutated proteins. Setting: Locations included primary care and university hospitals. Results: Family members with CH, mental retardation, and goiter were compound heterozygous for c.886C→T (p.R277X) and g.IVS35+1delG. For c.886C→T, a founder effect cannot be excluded, and its transcription was hardly detectable. g.IVS35+1delG caused an in-frame deletion in exon 35 and produced a protein that, although synthesized, could not be secreted. Ultrastructural analyses showed morphological changes consistent with an endoplasmic reticulum storage disease. Conclusion: The shorter thyroglobulin resulting from the novel g.IVS35+1delG was retained within the endoplasmic reticulum of thyrocytes,andtogether with p.R227X caused severe hypothyroidism with goiter. p.R277X, the most commonly described TG mutation, is caused by a TG exon-7 highly mutation-prone region, and the possibility thatsomecases were introduced to South America from Galicia cannot be excluded.Fil: Peteiro Gonzalez, D.. Universidad de Santiago de Compostela; EspañaFil: Lee, J.. Universidad de Santiago de Compostela; EspañaFil: Rodriguez Fontan, J.. University of Michigan; Estados UnidosFil: Castro Piedras, I.. Universidad de Santiago de Compostela; España. Texas Tech University; Estados UnidosFil: Cameselle Teijeiro, J.. Universidad de Santiago de Compostela; EspañaFil: Beiras, A.. Universidad de Santiago de Compostela; EspañaFil: Bravo, S. B.. Universidad de Santiago de Compostela; EspañaFil: Alvarez, C. V.. Universidad de Santiago de Compostela; EspañaFil: Hardy, D. M.. Texas Tech University; Estados UnidosFil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Arvan, P.. Universidad de Santiago de Compostela; España. University of Michigan; Estados UnidosFil: Lado Abeal, Joaquin. Universidad de Santiago de Compostela; España. Texas Tech University; Estados UnidosEndocrine Society2010-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/67719Peteiro Gonzalez, D.; Lee, J.; Rodriguez Fontan, J.; Castro Piedras, I.; Cameselle Teijeiro, J.; et al.; New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 95; 7; 7-2010; 3522-35260021-972X1945-7197CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1210/jc.2009-2109info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jcem/article/95/7/3522/2596814info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:56:04Zoai:ri.conicet.gov.ar:11336/67719instacron: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:34982025-09-03 09:56:04.83CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter
title New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter
spellingShingle New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter
Peteiro Gonzalez, D.
Congenital Goiter
Hypothyroidism
Thyroglobulin
Mutation
title_short New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter
title_full New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter
title_fullStr New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter
title_full_unstemmed New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter
title_sort New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter
dc.creator.none.fl_str_mv Peteiro Gonzalez, D.
Lee, J.
Rodriguez Fontan, J.
Castro Piedras, I.
Cameselle Teijeiro, J.
Beiras, A.
Bravo, S. B.
Alvarez, C. V.
Hardy, D. M.
Targovnik, Hector Manuel
Arvan, P.
Lado Abeal, Joaquin
author Peteiro Gonzalez, D.
author_facet Peteiro Gonzalez, D.
Lee, J.
Rodriguez Fontan, J.
Castro Piedras, I.
Cameselle Teijeiro, J.
Beiras, A.
Bravo, S. B.
Alvarez, C. V.
Hardy, D. M.
Targovnik, Hector Manuel
Arvan, P.
Lado Abeal, Joaquin
author_role author
author2 Lee, J.
Rodriguez Fontan, J.
Castro Piedras, I.
Cameselle Teijeiro, J.
Beiras, A.
Bravo, S. B.
Alvarez, C. V.
Hardy, D. M.
Targovnik, Hector Manuel
Arvan, P.
Lado Abeal, Joaquin
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Congenital Goiter
Hypothyroidism
Thyroglobulin
Mutation
topic Congenital Goiter
Hypothyroidism
Thyroglobulin
Mutation
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: Thyroglobulin (TG) gene mutations cause congenital hypothyroidism (CH) with goiter. A founder effect has been proposed for some frequent mutations. Mutated proteins have a defect in intracellular transport causing intracellular retention with ultrastructural changes that resemble an endoplasmic reticulum storage disease. Objective: To reveal new aspects of thyroglobulin pathophysiology through clinical, cellular, molecular, and genetic studies in a family presenting with CH due to TG mutations from Galicia, an iodine-deficient area of Spain. Design: The included clinical evaluation of family members, DNA sequencing for TG gene mutation and haplotyping analysis, ultrastructural analysis of thyroid tissue specimens from affected subjects, analysis of effects of mutations found on TG gene transcription, and in vitro studies of cellular production and secretion of mutated proteins. Setting: Locations included primary care and university hospitals. Results: Family members with CH, mental retardation, and goiter were compound heterozygous for c.886C→T (p.R277X) and g.IVS35+1delG. For c.886C→T, a founder effect cannot be excluded, and its transcription was hardly detectable. g.IVS35+1delG caused an in-frame deletion in exon 35 and produced a protein that, although synthesized, could not be secreted. Ultrastructural analyses showed morphological changes consistent with an endoplasmic reticulum storage disease. Conclusion: The shorter thyroglobulin resulting from the novel g.IVS35+1delG was retained within the endoplasmic reticulum of thyrocytes,andtogether with p.R227X caused severe hypothyroidism with goiter. p.R277X, the most commonly described TG mutation, is caused by a TG exon-7 highly mutation-prone region, and the possibility thatsomecases were introduced to South America from Galicia cannot be excluded.
Fil: Peteiro Gonzalez, D.. Universidad de Santiago de Compostela; España
Fil: Lee, J.. Universidad de Santiago de Compostela; España
Fil: Rodriguez Fontan, J.. University of Michigan; Estados Unidos
Fil: Castro Piedras, I.. Universidad de Santiago de Compostela; España. Texas Tech University; Estados Unidos
Fil: Cameselle Teijeiro, J.. Universidad de Santiago de Compostela; España
Fil: Beiras, A.. Universidad de Santiago de Compostela; España
Fil: Bravo, S. B.. Universidad de Santiago de Compostela; España
Fil: Alvarez, C. V.. Universidad de Santiago de Compostela; España
Fil: Hardy, D. M.. Texas Tech University; Estados Unidos
Fil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina
Fil: Arvan, P.. Universidad de Santiago de Compostela; España. University of Michigan; Estados Unidos
Fil: Lado Abeal, Joaquin. Universidad de Santiago de Compostela; España. Texas Tech University; Estados Unidos
description Context: Thyroglobulin (TG) gene mutations cause congenital hypothyroidism (CH) with goiter. A founder effect has been proposed for some frequent mutations. Mutated proteins have a defect in intracellular transport causing intracellular retention with ultrastructural changes that resemble an endoplasmic reticulum storage disease. Objective: To reveal new aspects of thyroglobulin pathophysiology through clinical, cellular, molecular, and genetic studies in a family presenting with CH due to TG mutations from Galicia, an iodine-deficient area of Spain. Design: The included clinical evaluation of family members, DNA sequencing for TG gene mutation and haplotyping analysis, ultrastructural analysis of thyroid tissue specimens from affected subjects, analysis of effects of mutations found on TG gene transcription, and in vitro studies of cellular production and secretion of mutated proteins. Setting: Locations included primary care and university hospitals. Results: Family members with CH, mental retardation, and goiter were compound heterozygous for c.886C→T (p.R277X) and g.IVS35+1delG. For c.886C→T, a founder effect cannot be excluded, and its transcription was hardly detectable. g.IVS35+1delG caused an in-frame deletion in exon 35 and produced a protein that, although synthesized, could not be secreted. Ultrastructural analyses showed morphological changes consistent with an endoplasmic reticulum storage disease. Conclusion: The shorter thyroglobulin resulting from the novel g.IVS35+1delG was retained within the endoplasmic reticulum of thyrocytes,andtogether with p.R227X caused severe hypothyroidism with goiter. p.R277X, the most commonly described TG mutation, is caused by a TG exon-7 highly mutation-prone region, and the possibility thatsomecases were introduced to South America from Galicia cannot be excluded.
publishDate 2010
dc.date.none.fl_str_mv 2010-07
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/11336/67719
Peteiro Gonzalez, D.; Lee, J.; Rodriguez Fontan, J.; Castro Piedras, I.; Cameselle Teijeiro, J.; et al.; New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 95; 7; 7-2010; 3522-3526
0021-972X
1945-7197
CONICET Digital
CONICET
url http://hdl.handle.net/11336/67719
identifier_str_mv Peteiro Gonzalez, D.; Lee, J.; Rodriguez Fontan, J.; Castro Piedras, I.; Cameselle Teijeiro, J.; et al.; New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 95; 7; 7-2010; 3522-3526
0021-972X
1945-7197
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1210/jc.2009-2109
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jcem/article/95/7/3522/2596814
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
application/pdf
dc.publisher.none.fl_str_mv Endocrine Society
publisher.none.fl_str_mv Endocrine Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
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
_version_ 1842269382188728320
score 13.13397

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