The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation

Autores
Pardo, Viviane; Vono Toniolo, Jussara; Rubio, Ileana G. S.; Knobel, Meyer; Possato, Roberta F.; Targovnik, Hector Manuel; Kopp, Peter; Medeiros Neto, Geraldo
Año de publicación
2009
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Context: Thyroglobulin (TG) is a large glycoprotein and functions as a matrix for thyroid hormone synthesis. TG gene mutations give rise to goitrous congenital hypothyroidism (CH) with considerable phenotype variation. Objectives: The aim of the study was to report the genetic screening of 15 patients with CH due to TG gene mutations and to perform functional analysis of the p.A2215D mutation. Design: Clinical evaluation and DNA sequencing of the TG gene were performed in all patients. TG expression was analyzed in the goitrous tissue of one patient. Human cells were transfected with expression vectors containing mutated and wild-type human TG cDNA. Results: All patients had an absent rise of serum TG after stimulation with recombinant human TSH. Sequence analysis revealed three previously described mutations (p.A2215D, p.R277X, and g.IVS30+1G>T), and two novel mutations (p.Q2142X and g.IVS46-1G>A). Two known (g.IVS30+1G/p.A2215D and p.A2215D/p.R277X) and one novel (p.R277X/g.IVS46-1G>A) compound heterozygous constellations were also identified. Functional analysis indicated deficiency in TG synthesis, reduction of TG secretion, and retention of the mutant TG within the cell, leading to an endoplasmic reticulum storage disease, whereas small amounts of mutant TG were still secreted within the cell system. Conclusion: All studied patients were either homozygous or heterozygous for TG gene mutations. Two novel mutations have been detected, and we show that TG mutation p.A2215D promotes the retention of TG within the endoplasmic reticulum and reduces TG synthesis and secretion, causing mild hypothyroidism. In the presence of sufficient iodine supply, some patients with TG mutations are able to compensate the impaired hormonogenesis and generate thyroid hormone.
Fil: Pardo, Viviane. Universidade de Sao Paulo; Brasil
Fil: Vono Toniolo, Jussara. Universidade de Sao Paulo; Brasil
Fil: Rubio, Ileana G. S.. Universidade de Sao Paulo; Brasil
Fil: Knobel, Meyer. Universidade de Sao Paulo; Brasil
Fil: Possato, Roberta F.. Universidade de Sao Paulo; Brasil
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. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Kopp, Peter. Northwestern University; Estados Unidos
Fil: Medeiros Neto, Geraldo. Universidade de Sao Paulo; Brasil
Materia
THYROGLOBULIN
CONGENITAL HYPOTHYROIDISM
GENE MUTATION
FUNCTIONAL ANALYSIS
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:11336/113292
Acceder
id CONICETDig_e2a4214796f317b6806750a88cff5ce7
oai_identifier_str oai:ri.conicet.gov.ar:11336/113292
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variationPardo, VivianeVono Toniolo, JussaraRubio, Ileana G. S.Knobel, MeyerPossato, Roberta F.Targovnik, Hector ManuelKopp, PeterMedeiros Neto, GeraldoTHYROGLOBULINCONGENITAL HYPOTHYROIDISMGENE MUTATIONFUNCTIONAL ANALYSIShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Context: Thyroglobulin (TG) is a large glycoprotein and functions as a matrix for thyroid hormone synthesis. TG gene mutations give rise to goitrous congenital hypothyroidism (CH) with considerable phenotype variation. Objectives: The aim of the study was to report the genetic screening of 15 patients with CH due to TG gene mutations and to perform functional analysis of the p.A2215D mutation. Design: Clinical evaluation and DNA sequencing of the TG gene were performed in all patients. TG expression was analyzed in the goitrous tissue of one patient. Human cells were transfected with expression vectors containing mutated and wild-type human TG cDNA. Results: All patients had an absent rise of serum TG after stimulation with recombinant human TSH. Sequence analysis revealed three previously described mutations (p.A2215D, p.R277X, and g.IVS30+1G>T), and two novel mutations (p.Q2142X and g.IVS46-1G>A). Two known (g.IVS30+1G/p.A2215D and p.A2215D/p.R277X) and one novel (p.R277X/g.IVS46-1G>A) compound heterozygous constellations were also identified. Functional analysis indicated deficiency in TG synthesis, reduction of TG secretion, and retention of the mutant TG within the cell, leading to an endoplasmic reticulum storage disease, whereas small amounts of mutant TG were still secreted within the cell system. Conclusion: All studied patients were either homozygous or heterozygous for TG gene mutations. Two novel mutations have been detected, and we show that TG mutation p.A2215D promotes the retention of TG within the endoplasmic reticulum and reduces TG synthesis and secretion, causing mild hypothyroidism. In the presence of sufficient iodine supply, some patients with TG mutations are able to compensate the impaired hormonogenesis and generate thyroid hormone.Fil: Pardo, Viviane. Universidade de Sao Paulo; BrasilFil: Vono Toniolo, Jussara. Universidade de Sao Paulo; BrasilFil: Rubio, Ileana G. S.. Universidade de Sao Paulo; BrasilFil: Knobel, Meyer. Universidade de Sao Paulo; BrasilFil: Possato, Roberta F.. Universidade de Sao Paulo; BrasilFil: 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. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Kopp, Peter. Northwestern University; Estados UnidosFil: Medeiros Neto, Geraldo. Universidade de Sao Paulo; BrasilEndocrine Society2009-08-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/113292Pardo, Viviane; Vono Toniolo, Jussara; Rubio, Ileana G. S.; Knobel, Meyer; Possato, Roberta F.; et al.; The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 94; 8; 1-8-2009; 2938-29440021-972XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1210/jc.2009-0150info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jcem/article/94/8/2938/2597041info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:03:19Zoai:ri.conicet.gov.ar:11336/113292instacron: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:34982025-09-29 10:03:19.656CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation
title The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation
spellingShingle The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation
Pardo, Viviane
THYROGLOBULIN
CONGENITAL HYPOTHYROIDISM
GENE MUTATION
FUNCTIONAL ANALYSIS
title_short The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation
title_full The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation
title_fullStr The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation
title_full_unstemmed The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation
title_sort The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation
dc.creator.none.fl_str_mv Pardo, Viviane
Vono Toniolo, Jussara
Rubio, Ileana G. S.
Knobel, Meyer
Possato, Roberta F.
Targovnik, Hector Manuel
Kopp, Peter
Medeiros Neto, Geraldo
author Pardo, Viviane
author_facet Pardo, Viviane
Vono Toniolo, Jussara
Rubio, Ileana G. S.
Knobel, Meyer
Possato, Roberta F.
Targovnik, Hector Manuel
Kopp, Peter
Medeiros Neto, Geraldo
author_role author
author2 Vono Toniolo, Jussara
Rubio, Ileana G. S.
Knobel, Meyer
Possato, Roberta F.
Targovnik, Hector Manuel
Kopp, Peter
Medeiros Neto, Geraldo
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv THYROGLOBULIN
CONGENITAL HYPOTHYROIDISM
GENE MUTATION
FUNCTIONAL ANALYSIS
topic THYROGLOBULIN
CONGENITAL HYPOTHYROIDISM
GENE MUTATION
FUNCTIONAL ANALYSIS
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) is a large glycoprotein and functions as a matrix for thyroid hormone synthesis. TG gene mutations give rise to goitrous congenital hypothyroidism (CH) with considerable phenotype variation. Objectives: The aim of the study was to report the genetic screening of 15 patients with CH due to TG gene mutations and to perform functional analysis of the p.A2215D mutation. Design: Clinical evaluation and DNA sequencing of the TG gene were performed in all patients. TG expression was analyzed in the goitrous tissue of one patient. Human cells were transfected with expression vectors containing mutated and wild-type human TG cDNA. Results: All patients had an absent rise of serum TG after stimulation with recombinant human TSH. Sequence analysis revealed three previously described mutations (p.A2215D, p.R277X, and g.IVS30+1G>T), and two novel mutations (p.Q2142X and g.IVS46-1G>A). Two known (g.IVS30+1G/p.A2215D and p.A2215D/p.R277X) and one novel (p.R277X/g.IVS46-1G>A) compound heterozygous constellations were also identified. Functional analysis indicated deficiency in TG synthesis, reduction of TG secretion, and retention of the mutant TG within the cell, leading to an endoplasmic reticulum storage disease, whereas small amounts of mutant TG were still secreted within the cell system. Conclusion: All studied patients were either homozygous or heterozygous for TG gene mutations. Two novel mutations have been detected, and we show that TG mutation p.A2215D promotes the retention of TG within the endoplasmic reticulum and reduces TG synthesis and secretion, causing mild hypothyroidism. In the presence of sufficient iodine supply, some patients with TG mutations are able to compensate the impaired hormonogenesis and generate thyroid hormone.
Fil: Pardo, Viviane. Universidade de Sao Paulo; Brasil
Fil: Vono Toniolo, Jussara. Universidade de Sao Paulo; Brasil
Fil: Rubio, Ileana G. S.. Universidade de Sao Paulo; Brasil
Fil: Knobel, Meyer. Universidade de Sao Paulo; Brasil
Fil: Possato, Roberta F.. Universidade de Sao Paulo; Brasil
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. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Kopp, Peter. Northwestern University; Estados Unidos
Fil: Medeiros Neto, Geraldo. Universidade de Sao Paulo; Brasil
description Context: Thyroglobulin (TG) is a large glycoprotein and functions as a matrix for thyroid hormone synthesis. TG gene mutations give rise to goitrous congenital hypothyroidism (CH) with considerable phenotype variation. Objectives: The aim of the study was to report the genetic screening of 15 patients with CH due to TG gene mutations and to perform functional analysis of the p.A2215D mutation. Design: Clinical evaluation and DNA sequencing of the TG gene were performed in all patients. TG expression was analyzed in the goitrous tissue of one patient. Human cells were transfected with expression vectors containing mutated and wild-type human TG cDNA. Results: All patients had an absent rise of serum TG after stimulation with recombinant human TSH. Sequence analysis revealed three previously described mutations (p.A2215D, p.R277X, and g.IVS30+1G>T), and two novel mutations (p.Q2142X and g.IVS46-1G>A). Two known (g.IVS30+1G/p.A2215D and p.A2215D/p.R277X) and one novel (p.R277X/g.IVS46-1G>A) compound heterozygous constellations were also identified. Functional analysis indicated deficiency in TG synthesis, reduction of TG secretion, and retention of the mutant TG within the cell, leading to an endoplasmic reticulum storage disease, whereas small amounts of mutant TG were still secreted within the cell system. Conclusion: All studied patients were either homozygous or heterozygous for TG gene mutations. Two novel mutations have been detected, and we show that TG mutation p.A2215D promotes the retention of TG within the endoplasmic reticulum and reduces TG synthesis and secretion, causing mild hypothyroidism. In the presence of sufficient iodine supply, some patients with TG mutations are able to compensate the impaired hormonogenesis and generate thyroid hormone.
publishDate 2009
dc.date.none.fl_str_mv 2009-08-01
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/11336/113292
Pardo, Viviane; Vono Toniolo, Jussara; Rubio, Ileana G. S.; Knobel, Meyer; Possato, Roberta F.; et al.; The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 94; 8; 1-8-2009; 2938-2944
0021-972X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/113292
identifier_str_mv Pardo, Viviane; Vono Toniolo, Jussara; Rubio, Ileana G. S.; Knobel, Meyer; Possato, Roberta F.; et al.; The p.A2215D thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 94; 8; 1-8-2009; 2938-2944
0021-972X
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.2009-0150
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jcem/article/94/8/2938/2597041
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_ 1844613847880564736
score 13.070432

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