Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death

Autores
Zhang, Xiaohan; Kellogg, Aaron P.; Citterio, Cintia Eliana; Zhang, Hao; Larkin, Dennis; Morishita, Yoshiaki; Targovnik, Hector Manuel; Balbi, Viviana A.; Arvan, Peter
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. Here, we demonstrate that TGW2346R/W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibited no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine was synthesized, and brief treatment of TGrdw/rdw rats with antithyroid drug was lethal to the animals. When untreated, remarkably, thyroxine was synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they were iodinated and cannibalized by surrounding live thyrocytes. As the animals continued to grow goiters, circulating thyroxine increased. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provided the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.
Fil: Zhang, Xiaohan. University of Michigan; Estados Unidos
Fil: Kellogg, Aaron P.. University of Michigan; Estados Unidos
Fil: Citterio, Cintia Eliana. University of Michigan; Estados Unidos. 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. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina
Fil: Zhang, Hao. University of Michigan; Estados Unidos
Fil: Larkin, Dennis. University of Michigan; Estados Unidos
Fil: Morishita, Yoshiaki. University of Michigan; Estados Unidos
Fil: Targovnik, Hector Manuel. 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. 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: Balbi, Viviana A.. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de La Plata; Argentina
Fil: Arvan, Peter. University of Michigan; Estados Unidos
Materia
Endocrinology
Thyroid disease
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:11336/135560
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/135560
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell deathZhang, XiaohanKellogg, Aaron P.Citterio, Cintia ElianaZhang, HaoLarkin, DennisMorishita, YoshiakiTargovnik, Hector ManuelBalbi, Viviana A.Arvan, PeterEndocrinologyThyroid diseasehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. Here, we demonstrate that TGW2346R/W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibited no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine was synthesized, and brief treatment of TGrdw/rdw rats with antithyroid drug was lethal to the animals. When untreated, remarkably, thyroxine was synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they were iodinated and cannibalized by surrounding live thyrocytes. As the animals continued to grow goiters, circulating thyroxine increased. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provided the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.Fil: Zhang, Xiaohan. University of Michigan; Estados UnidosFil: Kellogg, Aaron P.. University of Michigan; Estados UnidosFil: Citterio, Cintia Eliana. University of Michigan; Estados Unidos. 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. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Zhang, Hao. University of Michigan; Estados UnidosFil: Larkin, Dennis. University of Michigan; Estados UnidosFil: Morishita, Yoshiaki. University of Michigan; Estados UnidosFil: Targovnik, Hector Manuel. 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. 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: Balbi, Viviana A.. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de La Plata; ArgentinaFil: Arvan, Peter. University of Michigan; Estados UnidosAmerican Society for Clinical Investigation2021-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/135560Zhang, Xiaohan; Kellogg, Aaron P.; Citterio, Cintia Eliana; Zhang, Hao; Larkin, Dennis; et al.; Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death; American Society for Clinical Investigation; JCI Insight; 6; 11; 6-2021; 1-172379-3708CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://insight.jci.org/articles/view/148496info:eu-repo/semantics/altIdentifier/doi/10.1172/jci.insight.148496info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:44:44Zoai:ri.conicet.gov.ar:11336/135560instacron: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:34982025-11-12 09:44:44.878CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death
title Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death
spellingShingle Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death
Zhang, Xiaohan
Endocrinology
Thyroid disease
title_short Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death
title_full Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death
title_fullStr Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death
title_full_unstemmed Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death
title_sort Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death
dc.creator.none.fl_str_mv Zhang, Xiaohan
Kellogg, Aaron P.
Citterio, Cintia Eliana
Zhang, Hao
Larkin, Dennis
Morishita, Yoshiaki
Targovnik, Hector Manuel
Balbi, Viviana A.
Arvan, Peter
author Zhang, Xiaohan
author_facet Zhang, Xiaohan
Kellogg, Aaron P.
Citterio, Cintia Eliana
Zhang, Hao
Larkin, Dennis
Morishita, Yoshiaki
Targovnik, Hector Manuel
Balbi, Viviana A.
Arvan, Peter
author_role author
author2 Kellogg, Aaron P.
Citterio, Cintia Eliana
Zhang, Hao
Larkin, Dennis
Morishita, Yoshiaki
Targovnik, Hector Manuel
Balbi, Viviana A.
Arvan, Peter
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Endocrinology
Thyroid disease
topic Endocrinology
Thyroid disease
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. Here, we demonstrate that TGW2346R/W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibited no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine was synthesized, and brief treatment of TGrdw/rdw rats with antithyroid drug was lethal to the animals. When untreated, remarkably, thyroxine was synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they were iodinated and cannibalized by surrounding live thyrocytes. As the animals continued to grow goiters, circulating thyroxine increased. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provided the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.
Fil: Zhang, Xiaohan. University of Michigan; Estados Unidos
Fil: Kellogg, Aaron P.. University of Michigan; Estados Unidos
Fil: Citterio, Cintia Eliana. University of Michigan; Estados Unidos. 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. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina
Fil: Zhang, Hao. University of Michigan; Estados Unidos
Fil: Larkin, Dennis. University of Michigan; Estados Unidos
Fil: Morishita, Yoshiaki. University of Michigan; Estados Unidos
Fil: Targovnik, Hector Manuel. 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. 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: Balbi, Viviana A.. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de La Plata; Argentina
Fil: Arvan, Peter. University of Michigan; Estados Unidos
description Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. Here, we demonstrate that TGW2346R/W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibited no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine was synthesized, and brief treatment of TGrdw/rdw rats with antithyroid drug was lethal to the animals. When untreated, remarkably, thyroxine was synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they were iodinated and cannibalized by surrounding live thyrocytes. As the animals continued to grow goiters, circulating thyroxine increased. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provided the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.
publishDate 2021
dc.date.none.fl_str_mv 2021-06
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/11336/135560
Zhang, Xiaohan; Kellogg, Aaron P.; Citterio, Cintia Eliana; Zhang, Hao; Larkin, Dennis; et al.; Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death; American Society for Clinical Investigation; JCI Insight; 6; 11; 6-2021; 1-17
2379-3708
CONICET Digital
CONICET
url http://hdl.handle.net/11336/135560
identifier_str_mv Zhang, Xiaohan; Kellogg, Aaron P.; Citterio, Cintia Eliana; Zhang, Hao; Larkin, Dennis; et al.; Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death; American Society for Clinical Investigation; JCI Insight; 6; 11; 6-2021; 1-17
2379-3708
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://insight.jci.org/articles/view/148496
info:eu-repo/semantics/altIdentifier/doi/10.1172/jci.insight.148496
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
application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
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
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score 13.24909

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