Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening

Autores
Baquedano, María Sonia; Ciaccio, Marta Graciela Cristina; Dujovne, Noelia; Herzovich, Viviana; Longueira, Yesica Soledad; Warman, Diana Mónica; Rivarola, Marco Aurelio; Belgorosky, Alicia
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Context: Patients with TSH-β subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. Objective: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-β subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. Results: Patient 1 had a homozygous G to A nucleotide change at the 5′ donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-β subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. Conclusions: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.
Fil: Baquedano, María Sonia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Ciaccio, Marta Graciela Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Dujovne, Noelia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Herzovich, Viviana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Longueira, Yesica Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Warman, Diana Mónica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Rivarola, Marco Aurelio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Materia
TSH-Betha subunit defects
Congenital hypothyroidism
Neonatal TSH Screening
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:11336/252604
Acceder
id CONICETDig_d0f6b375ff6d1600bf7e1a2ab56fbd57
oai_identifier_str oai:ri.conicet.gov.ar:11336/252604
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH ScreeningBaquedano, María SoniaCiaccio, Marta Graciela CristinaDujovne, NoeliaHerzovich, VivianaLongueira, Yesica SoledadWarman, Diana MónicaRivarola, Marco AurelioBelgorosky, AliciaTSH-Betha subunit defectsCongenital hypothyroidismNeonatal TSH Screeninghttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Context: Patients with TSH-β subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. Objective: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-β subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. Results: Patient 1 had a homozygous G to A nucleotide change at the 5′ donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-β subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. Conclusions: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.Fil: Baquedano, María Sonia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ciaccio, Marta Graciela Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Dujovne, Noelia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Herzovich, Viviana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Longueira, Yesica Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Warman, Diana Mónica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Rivarola, Marco Aurelio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaEndocrine Society2010-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/252604Baquedano, María Sonia; Ciaccio, Marta Graciela Cristina; Dujovne, Noelia; Herzovich, Viviana; Longueira, Yesica Soledad; et al.; Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 95; 9; 6-2010; 98-1030021-972XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jcem/article-abstract/95/9/E98/2835186info:eu-repo/semantics/altIdentifier/doi/10.1210/jc.2010-0223info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:49:26Zoai:ri.conicet.gov.ar:11336/252604instacron: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 09:49:26.837CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
title Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
spellingShingle Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
Baquedano, María Sonia
TSH-Betha subunit defects
Congenital hypothyroidism
Neonatal TSH Screening
title_short Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
title_full Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
title_fullStr Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
title_full_unstemmed Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
title_sort Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening
dc.creator.none.fl_str_mv Baquedano, María Sonia
Ciaccio, Marta Graciela Cristina
Dujovne, Noelia
Herzovich, Viviana
Longueira, Yesica Soledad
Warman, Diana Mónica
Rivarola, Marco Aurelio
Belgorosky, Alicia
author Baquedano, María Sonia
author_facet Baquedano, María Sonia
Ciaccio, Marta Graciela Cristina
Dujovne, Noelia
Herzovich, Viviana
Longueira, Yesica Soledad
Warman, Diana Mónica
Rivarola, Marco Aurelio
Belgorosky, Alicia
author_role author
author2 Ciaccio, Marta Graciela Cristina
Dujovne, Noelia
Herzovich, Viviana
Longueira, Yesica Soledad
Warman, Diana Mónica
Rivarola, Marco Aurelio
Belgorosky, Alicia
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TSH-Betha subunit defects
Congenital hypothyroidism
Neonatal TSH Screening
topic TSH-Betha subunit defects
Congenital hypothyroidism
Neonatal TSH Screening
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Context: Patients with TSH-β subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. Objective: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-β subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. Results: Patient 1 had a homozygous G to A nucleotide change at the 5′ donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-β subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. Conclusions: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.
Fil: Baquedano, María Sonia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Ciaccio, Marta Graciela Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Dujovne, Noelia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Herzovich, Viviana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Longueira, Yesica Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Warman, Diana Mónica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Rivarola, Marco Aurelio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
description Context: Patients with TSH-β subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. Objective: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-β subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. Results: Patient 1 had a homozygous G to A nucleotide change at the 5′ donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-β subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. Conclusions: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.
publishDate 2010
dc.date.none.fl_str_mv 2010-06
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/11336/252604
Baquedano, María Sonia; Ciaccio, Marta Graciela Cristina; Dujovne, Noelia; Herzovich, Viviana; Longueira, Yesica Soledad; et al.; Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 95; 9; 6-2010; 98-103
0021-972X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/252604
identifier_str_mv Baquedano, María Sonia; Ciaccio, Marta Graciela Cristina; Dujovne, Noelia; Herzovich, Viviana; Longueira, Yesica Soledad; et al.; Two Novel Mutations of the TSH-β Subunit Gene Underlying Congenital Central Hypothyroidism Undetectable in Neonatal TSH Screening; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 95; 9; 6-2010; 98-103
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/url/https://academic.oup.com/jcem/article-abstract/95/9/E98/2835186
info:eu-repo/semantics/altIdentifier/doi/10.1210/jc.2010-0223
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
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
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score 13.13397

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