Mutations in JMJD1C are involved in Rett syndrome and intellectual disability

PURPOSE: Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are...

Descripción completa

Detalles Bibliográficos
Autores: Sáez, Mauricio A., Pérez Jurado, Luis Alberto, Esteller, Manel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/26918
Acceso en línea:http://hdl.handle.net/10230/26918
http://dx.doi.org/10.1038/gim.2015.100
Access Level:acceso abierto
Palabra clave:Autisme -- Aspectes genètics
Autism
Intellectual disability
Mutational screening
Rett syndrome
id ES_fd72e07748aa4e2cf462fe86e5f27491
oai_identifier_str oai:repositori.upf.edu:10230/26918
network_acronym_str ES
network_name_str España
repository_id_str
spelling Mutations in JMJD1C are involved in Rett syndrome and intellectual disabilitySáez, Mauricio A.Pérez Jurado, Luis AlbertoEsteller, ManelAutisme -- Aspectes genèticsAutismIntellectual disabilityMutational screeningRett syndromePURPOSE: Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders. METHODS: We performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect. RESULTS: We found seven JMJD1C variants that were not present in any control sample ( 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity. CONCLUSIONS: Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.Genet Med 18 1, 378-385.This study was supported by the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement PITN-GA-2012–316758 of the EPITRAIN project and PITN-GA-2009–238242 of DISCHROM; ERC grant agreement 268626 of the EPINORC project; the E-RARE EuroRETT network (Carlos III Health Institute project PI071327); the Fondation Lejeune (France); MINECO projects SAF2011-22803 and CSD2006-00049; the Cellex Foundation; the Botín Foundation; the Catalan Association for Rett Syndrome; Fundación Alicia Koplowitz 2011 Grant AKOPLOWITZ11_006; the FIS project PI1002512; Grants PI10/01422, PI13/00285, CA10/01474, RD06/0020/1050, RD12/0036/008, and 2009-SGR293; and the Health and Science Departments of the Catalan government (Generalitat de Catalunya). K.S. and P.P. are EPITRAIN Research Fellows. M.E. is an ICREA Research Professor.Lippincott Williams & Wilkins201620162016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/26918http://dx.doi.org/10.1038/gim.2015.100reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésGenetics in medicine. 2016; 18(4): 378-385info:eu-repo/grantAgreement/ES/3PN/SAF2011-22803This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, /nusers will need to obtain permission from the license holder to reproduce the material.http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/269182026-06-12T07:21:37Z
dc.title.none.fl_str_mv Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
title Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
spellingShingle Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
Sáez, Mauricio A.
Autisme -- Aspectes genètics
Autism
Intellectual disability
Mutational screening
Rett syndrome
title_short Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
title_full Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
title_fullStr Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
title_full_unstemmed Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
title_sort Mutations in JMJD1C are involved in Rett syndrome and intellectual disability
dc.creator.none.fl_str_mv Sáez, Mauricio A.
Pérez Jurado, Luis Alberto
Esteller, Manel
author Sáez, Mauricio A.
author_facet Sáez, Mauricio A.
Pérez Jurado, Luis Alberto
Esteller, Manel
author_role author
author2 Pérez Jurado, Luis Alberto
Esteller, Manel
author2_role author
author
dc.subject.none.fl_str_mv Autisme -- Aspectes genètics
Autism
Intellectual disability
Mutational screening
Rett syndrome
topic Autisme -- Aspectes genètics
Autism
Intellectual disability
Mutational screening
Rett syndrome
description PURPOSE: Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders. METHODS: We performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect. RESULTS: We found seven JMJD1C variants that were not present in any control sample ( 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity. CONCLUSIONS: Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.Genet Med 18 1, 378-385.
publishDate 2016
dc.date.none.fl_str_mv 2016
2016
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/26918
http://dx.doi.org/10.1038/gim.2015.100
url http://hdl.handle.net/10230/26918
http://dx.doi.org/10.1038/gim.2015.100
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Genetics in medicine. 2016; 18(4): 378-385
info:eu-repo/grantAgreement/ES/3PN/SAF2011-22803
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Lippincott Williams & Wilkins
publisher.none.fl_str_mv Lippincott Williams & Wilkins
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425540681695232
score 15,81155

Similares en LA Referencia