Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis

Autores
Weedon, M. N.; Cebola, I.; Patch, A. M.; Flanagan, S.; De Franco, E.; Caswell, R.; Rodríguez Seguí, Santiago Andrés; Shaw Smith, C.; Cho, C.; Allen, H. L.; Houghton, J.; Roth, C. L.; Chen, R.; Hussain, K.; Marsh, P.; Vallier, L.; Murray, A.; International Pancreatic Agenesis Consortium; Ellard, S.; Ferrer, J.; Hattersley, A. T.
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ∼400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.
Fil: Weedon, M. N.. University of Exeter; Reino Unido
Fil: Cebola, I.. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Imperial College London; Reino Unido
Fil: Patch, A. M.. University of Exeter; Reino Unido
Fil: Flanagan, S.. University of Exeter; Reino Unido
Fil: De Franco, E.. University of Exeter; Reino Unido
Fil: Caswell, R.. University of Exeter; Reino Unido
Fil: Rodríguez Seguí, Santiago Andrés. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Shaw Smith, C.. University of Exeter; Reino Unido
Fil: Cho, C.. Anne McLaren Laboratory for Regenerative Medicine; Reino Unido
Fil: Allen, H. L.. University of Exeter; Reino Unido
Fil: Houghton, J.. University of Exeter; Reino Unido
Fil: Roth, C. L.. Seattle Children’s Hospital Research Institute; Estados Unidos
Fil: Chen, R.. King’s College London; Reino Unido
Fil: Hussain, K.. University College London; Reino Unido
Fil: Marsh, P.. King’s College London; Reino Unido
Fil: Vallier, L.. Anne McLaren Laboratory for Regenerative Medicine; Reino Unido
Fil: Murray, A.. University of Exeter; Reino Unido
Fil: International Pancreatic Agenesis Consortium. No especifica;
Fil: Ellard, S.. University of Exeter; Reino Unido
Fil: Ferrer, J.. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Imperial College London; Reino Unido
Fil: Hattersley, A. T.. University of Exeter; Reino Unido
Materia
PANCREAS
AGENESIS
PTF1A
ENHANCER
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:11336/86053
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/86053
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesisWeedon, M. N.Cebola, I.Patch, A. M.Flanagan, S.De Franco, E.Caswell, R.Rodríguez Seguí, Santiago AndrésShaw Smith, C.Cho, C.Allen, H. L.Houghton, J.Roth, C. L.Chen, R.Hussain, K.Marsh, P.Vallier, L.Murray, A.International Pancreatic Agenesis ConsortiumEllard, S.Ferrer, J.Hattersley, A. T.PANCREASAGENESISPTF1AENHANCERhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ∼400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.Fil: Weedon, M. N.. University of Exeter; Reino UnidoFil: Cebola, I.. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Imperial College London; Reino UnidoFil: Patch, A. M.. University of Exeter; Reino UnidoFil: Flanagan, S.. University of Exeter; Reino UnidoFil: De Franco, E.. University of Exeter; Reino UnidoFil: Caswell, R.. University of Exeter; Reino UnidoFil: Rodríguez Seguí, Santiago Andrés. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Shaw Smith, C.. University of Exeter; Reino UnidoFil: Cho, C.. Anne McLaren Laboratory for Regenerative Medicine; Reino UnidoFil: Allen, H. L.. University of Exeter; Reino UnidoFil: Houghton, J.. University of Exeter; Reino UnidoFil: Roth, C. L.. Seattle Children’s Hospital Research Institute; Estados UnidosFil: Chen, R.. King’s College London; Reino UnidoFil: Hussain, K.. University College London; Reino UnidoFil: Marsh, P.. King’s College London; Reino UnidoFil: Vallier, L.. Anne McLaren Laboratory for Regenerative Medicine; Reino UnidoFil: Murray, A.. University of Exeter; Reino UnidoFil: International Pancreatic Agenesis Consortium. No especifica;Fil: Ellard, S.. University of Exeter; Reino UnidoFil: Ferrer, J.. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Imperial College London; Reino UnidoFil: Hattersley, A. T.. University of Exeter; Reino UnidoNature Publishing Group2014-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/86053Weedon, M. N.; Cebola, I.; Patch, A. M.; Flanagan, S.; De Franco, E.; et al.; Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis; Nature Publishing Group; Nature Genetics; 46; 1; 1-2014; 61-641061-4036CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/ng.2826info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ng.2826info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:34:59Zoai:ri.conicet.gov.ar:11336/86053instacron: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 09:34:59.486CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis
title Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis
spellingShingle Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis
Weedon, M. N.
PANCREAS
AGENESIS
PTF1A
ENHANCER
title_short Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis
title_full Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis
title_fullStr Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis
title_full_unstemmed Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis
title_sort Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis
dc.creator.none.fl_str_mv Weedon, M. N.
Cebola, I.
Patch, A. M.
Flanagan, S.
De Franco, E.
Caswell, R.
Rodríguez Seguí, Santiago Andrés
Shaw Smith, C.
Cho, C.
Allen, H. L.
Houghton, J.
Roth, C. L.
Chen, R.
Hussain, K.
Marsh, P.
Vallier, L.
Murray, A.
International Pancreatic Agenesis Consortium
Ellard, S.
Ferrer, J.
Hattersley, A. T.
author Weedon, M. N.
author_facet Weedon, M. N.
Cebola, I.
Patch, A. M.
Flanagan, S.
De Franco, E.
Caswell, R.
Rodríguez Seguí, Santiago Andrés
Shaw Smith, C.
Cho, C.
Allen, H. L.
Houghton, J.
Roth, C. L.
Chen, R.
Hussain, K.
Marsh, P.
Vallier, L.
Murray, A.
International Pancreatic Agenesis Consortium
Ellard, S.
Ferrer, J.
Hattersley, A. T.
author_role author
author2 Cebola, I.
Patch, A. M.
Flanagan, S.
De Franco, E.
Caswell, R.
Rodríguez Seguí, Santiago Andrés
Shaw Smith, C.
Cho, C.
Allen, H. L.
Houghton, J.
Roth, C. L.
Chen, R.
Hussain, K.
Marsh, P.
Vallier, L.
Murray, A.
International Pancreatic Agenesis Consortium
Ellard, S.
Ferrer, J.
Hattersley, A. T.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PANCREAS
AGENESIS
PTF1A
ENHANCER
topic PANCREAS
AGENESIS
PTF1A
ENHANCER
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ∼400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.
Fil: Weedon, M. N.. University of Exeter; Reino Unido
Fil: Cebola, I.. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Imperial College London; Reino Unido
Fil: Patch, A. M.. University of Exeter; Reino Unido
Fil: Flanagan, S.. University of Exeter; Reino Unido
Fil: De Franco, E.. University of Exeter; Reino Unido
Fil: Caswell, R.. University of Exeter; Reino Unido
Fil: Rodríguez Seguí, Santiago Andrés. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Shaw Smith, C.. University of Exeter; Reino Unido
Fil: Cho, C.. Anne McLaren Laboratory for Regenerative Medicine; Reino Unido
Fil: Allen, H. L.. University of Exeter; Reino Unido
Fil: Houghton, J.. University of Exeter; Reino Unido
Fil: Roth, C. L.. Seattle Children’s Hospital Research Institute; Estados Unidos
Fil: Chen, R.. King’s College London; Reino Unido
Fil: Hussain, K.. University College London; Reino Unido
Fil: Marsh, P.. King’s College London; Reino Unido
Fil: Vallier, L.. Anne McLaren Laboratory for Regenerative Medicine; Reino Unido
Fil: Murray, A.. University of Exeter; Reino Unido
Fil: International Pancreatic Agenesis Consortium. No especifica;
Fil: Ellard, S.. University of Exeter; Reino Unido
Fil: Ferrer, J.. Institut d’Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas; España. Imperial College London; Reino Unido
Fil: Hattersley, A. T.. University of Exeter; Reino Unido
description The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ∼400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.
publishDate 2014
dc.date.none.fl_str_mv 2014-01
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/11336/86053
Weedon, M. N.; Cebola, I.; Patch, A. M.; Flanagan, S.; De Franco, E.; et al.; Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis; Nature Publishing Group; Nature Genetics; 46; 1; 1-2014; 61-64
1061-4036
CONICET Digital
CONICET
url http://hdl.handle.net/11336/86053
identifier_str_mv Weedon, M. N.; Cebola, I.; Patch, A. M.; Flanagan, S.; De Franco, E.; et al.; Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis; Nature Publishing Group; Nature Genetics; 46; 1; 1-2014; 61-64
1061-4036
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/ng.2826
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ng.2826
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 Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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 13.070432

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