Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Hypomyelinating leukodystrophy; Inborn errors of metabolism; Phosphoinositol

Bibliographic Details
Authors: Verdura, Edgard, Rodriguez-Palmero Seuma, Agusti, Vélez Santamaria, Valentina, Planas Serra, Laura, de la Calle, Irene, Raspall Chaure, Miquel
Format: article
Status:Published version
Publication Date:2021
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:11351/7675
Online Access:https://hdl.handle.net/11351/7675
http://hdl.handle.net/11351/7675
Access Level:Open access
Keyword:Pediatria
Sistema nerviós - Malalties - Aspectes genètics
Mielina - Malalties - Aspectes genètics
PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurodevelopmental Disorders
Other subheadings::Other subheadings::Other subheadings::/genetics
DISCIPLINES AND OCCUPATIONS::Health Occupations::Medicine::Pediatrics
DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Brain Diseases, Metabolic::Brain Diseases, Metabolic, Inborn::Hereditary Central Nervous System Demyelinating Diseases
PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos del desarrollo neurológico
Otros calificadores::Otros calificadores::Otros calificadores::/genética
DISCIPLINAS Y OCUPACIONES::profesiones sanitarias::medicina::pediatría
ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebrales metabólicas::enfermedades cerebrales metabólicas congénitas::enfermedades desmielinizantes hereditarias del sistema nervioso central
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oai_identifier_str oai:recercat.cat:11351/7675
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
title Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
spellingShingle Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
Verdura, Edgard
Pediatria
Sistema nerviós - Malalties - Aspectes genètics
Mielina - Malalties - Aspectes genètics
PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurodevelopmental Disorders
Other subheadings::Other subheadings::Other subheadings::/genetics
DISCIPLINES AND OCCUPATIONS::Health Occupations::Medicine::Pediatrics
DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Brain Diseases, Metabolic::Brain Diseases, Metabolic, Inborn::Hereditary Central Nervous System Demyelinating Diseases
PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos del desarrollo neurológico
Otros calificadores::Otros calificadores::Otros calificadores::/genética
DISCIPLINAS Y OCUPACIONES::profesiones sanitarias::medicina::pediatría
ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebrales metabólicas::enfermedades cerebrales metabólicas congénitas::enfermedades desmielinizantes hereditarias del sistema nervioso central
title_short Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
title_full Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
title_fullStr Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
title_full_unstemmed Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
title_sort Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
dc.creator.none.fl_str_mv Verdura, Edgard
Rodriguez-Palmero Seuma, Agusti
Vélez Santamaria, Valentina
Planas Serra, Laura
de la Calle, Irene
Raspall Chaure, Miquel
author Verdura, Edgard
author_facet Verdura, Edgard
Rodriguez-Palmero Seuma, Agusti
Vélez Santamaria, Valentina
Planas Serra, Laura
de la Calle, Irene
Raspall Chaure, Miquel
author_role author
author2 Rodriguez-Palmero Seuma, Agusti
Vélez Santamaria, Valentina
Planas Serra, Laura
de la Calle, Irene
Raspall Chaure, Miquel
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Institut Català de la Salut
[Verdura E, Planas-Serra L] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Centre for Biomedical Research in Network on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain. [Rodríguez-Palmero A] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Catalonia, Spain. [Vélez-Santamaria V] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain. [de la Calle I] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. [Raspall-Chaure M] Grup de Recerca en Neurologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
dc.subject.none.fl_str_mv Pediatria
Sistema nerviós - Malalties - Aspectes genètics
Mielina - Malalties - Aspectes genètics
PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurodevelopmental Disorders
Other subheadings::Other subheadings::Other subheadings::/genetics
DISCIPLINES AND OCCUPATIONS::Health Occupations::Medicine::Pediatrics
DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Brain Diseases, Metabolic::Brain Diseases, Metabolic, Inborn::Hereditary Central Nervous System Demyelinating Diseases
PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos del desarrollo neurológico
Otros calificadores::Otros calificadores::Otros calificadores::/genética
DISCIPLINAS Y OCUPACIONES::profesiones sanitarias::medicina::pediatría
ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebrales metabólicas::enfermedades cerebrales metabólicas congénitas::enfermedades desmielinizantes hereditarias del sistema nervioso central
topic Pediatria
Sistema nerviós - Malalties - Aspectes genètics
Mielina - Malalties - Aspectes genètics
PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurodevelopmental Disorders
Other subheadings::Other subheadings::Other subheadings::/genetics
DISCIPLINES AND OCCUPATIONS::Health Occupations::Medicine::Pediatrics
DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Brain Diseases, Metabolic::Brain Diseases, Metabolic, Inborn::Hereditary Central Nervous System Demyelinating Diseases
PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos del desarrollo neurológico
Otros calificadores::Otros calificadores::Otros calificadores::/genética
DISCIPLINAS Y OCUPACIONES::profesiones sanitarias::medicina::pediatría
ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebrales metabólicas::enfermedades cerebrales metabólicas congénitas::enfermedades desmielinizantes hereditarias del sistema nervioso central
description Hypomyelinating leukodystrophy; Inborn errors of metabolism; Phosphoinositol
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
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 https://hdl.handle.net/11351/7675
http://hdl.handle.net/11351/7675
url https://hdl.handle.net/11351/7675
http://hdl.handle.net/11351/7675
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Brain;144(9)
https://doi.org/10.1093/brain/awab124
dc.rights.none.fl_str_mv Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv Scientia
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophyVerdura, EdgardRodriguez-Palmero Seuma, AgustiVélez Santamaria, ValentinaPlanas Serra, Laurade la Calle, IreneRaspall Chaure, MiquelPediatriaSistema nerviós - Malalties - Aspectes genèticsMielina - Malalties - Aspectes genèticsPSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurodevelopmental DisordersOther subheadings::Other subheadings::Other subheadings::/geneticsDISCIPLINES AND OCCUPATIONS::Health Occupations::Medicine::PediatricsDISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Brain Diseases, Metabolic::Brain Diseases, Metabolic, Inborn::Hereditary Central Nervous System Demyelinating DiseasesPSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos del desarrollo neurológicoOtros calificadores::Otros calificadores::Otros calificadores::/genéticaDISCIPLINAS Y OCUPACIONES::profesiones sanitarias::medicina::pediatríaENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebrales metabólicas::enfermedades cerebrales metabólicas congénitas::enfermedades desmielinizantes hereditarias del sistema nervioso centralHypomyelinating leukodystrophy; Inborn errors of metabolism; PhosphoinositolLeucodistrofia hipomielinizante; Errores innatos del metabolismo; FosfoinositolLeucodistròfia hipomielinizant; Errors innats del metabolisme; FosfoinositolPhosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients’ fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.We thank the CERCA Program/Generalitat de Catalunya for institutional support. This study was supported by grants from the Hesperia Foundation, the Asociación Española contra las Leucodistrofias (ALE-ELA España), the Autonomous Government of Catalonia (SGR 2017SGR1206 and PERIS program URD-Cat SLT002/16/00174) and the Center for Biomedical Research on Rare Diseases (CIBERER) (ACCI19-759 to A.P.). This study was also funded by Fundació La Marató de TV3 (595/C/2020) as well as Instituto de Salud Carlos III (FIS PI20/00758 to C.C.) (co-funded by European Regional Development Fund. ERDF, a way to build Europe). This study was also funded by the Instituto de Salud Carlos III (Rio Hortega, CM18/00145 to V.V.; PFIS, FI18/00141 to L.P.; and Sara Borrell, CD19/00221 to E.V.), co-funded by European Social Fund. ESF investing in your future; the Ministerio de Ciencia e Innovación y Universidades (Juan de la Cierva, FJCI-2016-28811 to E.V.), and the Center for Biomedical Research on Rare Diseases (CIBERER to M.R.). Sequencing and analysis of Patient 5 were performed by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, the National Heart, Lung and Blood Institute grants UM1 HG008900 and R01 HG009141 and the Chan Zuckerberg Initiative to the Rare Genomes Project. This work was in part supported by the association ‘Connaître les Syndromes Cérébelleux’ (CSC). This research received funding specifically appointed to the Department of Medical Sciences from the Italian Ministry for Education, University and Research (Ministero dell’istruzione, dell’università e della ricerca-MIUR) under the programme ‘Dipartimenti di Eccellenza 2018-2022’ Project code D15D18000410001. Whole-exome sequencing was performed as part of the Autism Sequencing Consortium and was supported by the NIMH (MH111661). D.R.A. and A.P. are members of the Undiagnosed Disease Network International (UDNI).Oxford University PressInstitut Català de la Salut[Verdura E, Planas-Serra L] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Centre for Biomedical Research in Network on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain. [Rodríguez-Palmero A] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Catalonia, Spain. [Vélez-Santamaria V] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain. [de la Calle I] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. [Raspall-Chaure M] Grup de Recerca en Neurologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, SpainVall d'Hebron Barcelona Hospital Campus202220222021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11351/7675http://hdl.handle.net/11351/7675Scientiareponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésBrain;144(9)https://doi.org/10.1093/brain/awab124Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:11351/76752026-05-29T05:05:01Z
score 15,81155

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