Knockout mice with pituitary malformations help identify human cases of hypopituitarism

Autores
Martínez Mayer, Julián Jorge; Brinkmeier, Michelle L.; O' Connell, Sean P.; Ukagwu, Arnold; Marti, Marcelo Adrian; Miras, Mirta; Forclaz, Maria V.; Benzrihen, Maria G.; Cheung, Leonard Y. M.; Camper, Sally A.; Ellsworth, Buffy S.; Raetzman, Lori T.; Pérez Millán, María Inés; Davis, Shannon W.
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS).Methods: The International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations.Results: Of the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features.Conclusions: The screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.
Fil: Martínez Mayer, Julián Jorge. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Brinkmeier, Michelle L.. University of Michigan; Estados Unidos
Fil: O' Connell, Sean P.. University of North Carolina; Estados Unidos
Fil: Ukagwu, Arnold. Southern Illinois University; Estados Unidos
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Miras, Mirta. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; Argentina
Fil: Forclaz, Maria V.. Hospital Nacional Profesor Alejandro Posadas; Argentina
Fil: Benzrihen, Maria G.. Hospital Nacional Profesor Alejandro Posadas; Argentina
Fil: Cheung, Leonard Y. M.. University of Michigan; Estados Unidos
Fil: Camper, Sally A.. University of Michigan; Estados Unidos
Fil: Ellsworth, Buffy S.. Southern Illinois University; Estados Unidos
Fil: Raetzman, Lori T.. University of Illinois; Estados Unidos
Fil: Pérez Millán, María Inés. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Davis, Shannon W.. University of North Carolina; Estados Unidos
Materia
Congenital hypopituitarism
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/238056
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Knockout mice with pituitary malformations help identify human cases of hypopituitarismMartínez Mayer, Julián JorgeBrinkmeier, Michelle L.O' Connell, Sean P.Ukagwu, ArnoldMarti, Marcelo AdrianMiras, MirtaForclaz, Maria V.Benzrihen, Maria G.Cheung, Leonard Y. M.Camper, Sally A.Ellsworth, Buffy S.Raetzman, Lori T.Pérez Millán, María InésDavis, Shannon W.Congenital hypopituitarismhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background: Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS).Methods: The International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations.Results: Of the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features.Conclusions: The screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.Fil: Martínez Mayer, Julián Jorge. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Brinkmeier, Michelle L.. University of Michigan; Estados UnidosFil: O' Connell, Sean P.. University of North Carolina; Estados UnidosFil: Ukagwu, Arnold. Southern Illinois University; Estados UnidosFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Miras, Mirta. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; ArgentinaFil: Forclaz, Maria V.. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Benzrihen, Maria G.. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Cheung, Leonard Y. M.. University of Michigan; Estados UnidosFil: Camper, Sally A.. University of Michigan; Estados UnidosFil: Ellsworth, Buffy S.. Southern Illinois University; Estados UnidosFil: Raetzman, Lori T.. University of Illinois; Estados UnidosFil: Pérez Millán, María Inés. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Davis, Shannon W.. University of North Carolina; Estados UnidosBioMed Central2024-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/238056Martínez Mayer, Julián Jorge; Brinkmeier, Michelle L.; O' Connell, Sean P.; Ukagwu, Arnold; Marti, Marcelo Adrian; et al.; Knockout mice with pituitary malformations help identify human cases of hypopituitarism; BioMed Central; Genome Medicine; 16; 1; 5-2024; 1-241756-994XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-024-01347-yinfo:eu-repo/semantics/altIdentifier/doi/10.1186/s13073-024-01347-yinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:56:27Zoai:ri.conicet.gov.ar:11336/238056instacron: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 09:56:28.135CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Knockout mice with pituitary malformations help identify human cases of hypopituitarism
title Knockout mice with pituitary malformations help identify human cases of hypopituitarism
spellingShingle Knockout mice with pituitary malformations help identify human cases of hypopituitarism
Martínez Mayer, Julián Jorge
Congenital hypopituitarism
title_short Knockout mice with pituitary malformations help identify human cases of hypopituitarism
title_full Knockout mice with pituitary malformations help identify human cases of hypopituitarism
title_fullStr Knockout mice with pituitary malformations help identify human cases of hypopituitarism
title_full_unstemmed Knockout mice with pituitary malformations help identify human cases of hypopituitarism
title_sort Knockout mice with pituitary malformations help identify human cases of hypopituitarism
dc.creator.none.fl_str_mv Martínez Mayer, Julián Jorge
Brinkmeier, Michelle L.
O' Connell, Sean P.
Ukagwu, Arnold
Marti, Marcelo Adrian
Miras, Mirta
Forclaz, Maria V.
Benzrihen, Maria G.
Cheung, Leonard Y. M.
Camper, Sally A.
Ellsworth, Buffy S.
Raetzman, Lori T.
Pérez Millán, María Inés
Davis, Shannon W.
author Martínez Mayer, Julián Jorge
author_facet Martínez Mayer, Julián Jorge
Brinkmeier, Michelle L.
O' Connell, Sean P.
Ukagwu, Arnold
Marti, Marcelo Adrian
Miras, Mirta
Forclaz, Maria V.
Benzrihen, Maria G.
Cheung, Leonard Y. M.
Camper, Sally A.
Ellsworth, Buffy S.
Raetzman, Lori T.
Pérez Millán, María Inés
Davis, Shannon W.
author_role author
author2 Brinkmeier, Michelle L.
O' Connell, Sean P.
Ukagwu, Arnold
Marti, Marcelo Adrian
Miras, Mirta
Forclaz, Maria V.
Benzrihen, Maria G.
Cheung, Leonard Y. M.
Camper, Sally A.
Ellsworth, Buffy S.
Raetzman, Lori T.
Pérez Millán, María Inés
Davis, Shannon W.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Congenital hypopituitarism
topic Congenital hypopituitarism
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Background: Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS).Methods: The International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations.Results: Of the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features.Conclusions: The screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.
Fil: Martínez Mayer, Julián Jorge. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Brinkmeier, Michelle L.. University of Michigan; Estados Unidos
Fil: O' Connell, Sean P.. University of North Carolina; Estados Unidos
Fil: Ukagwu, Arnold. Southern Illinois University; Estados Unidos
Fil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Miras, Mirta. Gobierno de la Provincia de Córdoba. Ministerio de Salud. Hospital de Niños de la Santísima Trinidad; Argentina
Fil: Forclaz, Maria V.. Hospital Nacional Profesor Alejandro Posadas; Argentina
Fil: Benzrihen, Maria G.. Hospital Nacional Profesor Alejandro Posadas; Argentina
Fil: Cheung, Leonard Y. M.. University of Michigan; Estados Unidos
Fil: Camper, Sally A.. University of Michigan; Estados Unidos
Fil: Ellsworth, Buffy S.. Southern Illinois University; Estados Unidos
Fil: Raetzman, Lori T.. University of Illinois; Estados Unidos
Fil: Pérez Millán, María Inés. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Davis, Shannon W.. University of North Carolina; Estados Unidos
description Background: Congenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS).Methods: The International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations.Results: Of the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features.Conclusions: The screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.
publishDate 2024
dc.date.none.fl_str_mv 2024-05
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/11336/238056
Martínez Mayer, Julián Jorge; Brinkmeier, Michelle L.; O' Connell, Sean P.; Ukagwu, Arnold; Marti, Marcelo Adrian; et al.; Knockout mice with pituitary malformations help identify human cases of hypopituitarism; BioMed Central; Genome Medicine; 16; 1; 5-2024; 1-24
1756-994X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/238056
identifier_str_mv Martínez Mayer, Julián Jorge; Brinkmeier, Michelle L.; O' Connell, Sean P.; Ukagwu, Arnold; Marti, Marcelo Adrian; et al.; Knockout mice with pituitary malformations help identify human cases of hypopituitarism; BioMed Central; Genome Medicine; 16; 1; 5-2024; 1-24
1756-994X
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://genomemedicine.biomedcentral.com/articles/10.1186/s13073-024-01347-y
info:eu-repo/semantics/altIdentifier/doi/10.1186/s13073-024-01347-y
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
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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