Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Phosphoinositides 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. P...

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Autores: Verdura, Edgard|||0000-0003-3856-2060, Rodríguez-Palmero, Agustí|||0000-0002-4141-5515, Vélez-Santamaria, Valentina, Planas-Serra, Laura|||0000-0002-2586-0897, de la Calle, Irene|||0000-0002-2227-1640, Raspall-Chaure, Miquel|||0000-0002-3132-3342, Roubertie, Agathe, Benkirane, Mehdi, Saettini, Francesco|||0000-0003-0767-3905, Pavinato, Lisa|||0000-0002-7630-8365, Mandrile, Giorgia, O'Leary, Melanie, O'Heir, Emily, Barredo, Estibaliz, Chacón, Almudena, Michaud, Vincent|||0000-0002-5788-392X, Goizet, Cyril, Ruiz, Montserrat|||0000-0003-0466-2653, Schlüter, Agatha|||0000-0001-6732-1528, Rouvet, Isabelle, Sala-Coromina, Júlia|||0000-0001-5116-6316, Fossati, Chiara, Iascone, Maria, Canonico, Francesco, Marcé-Grau, Anna|||0000-0001-5762-4023, de Souza, Precilla, Adams, David R., Casasnovas, Carlos|||0000-0002-7933-4681, Rehm, Heidi L., Mefford, Heather C.|||0000-0001-7188-522X, González Gutiérrez-Solana, Luis|||0000-0003-2890-4565, Brusco, Alfredo|||0000-0002-8318-7231, Koenig, Michel, Macaya Ruiz, Alfons|||0000-0001-7998-4185, Pujol, Aurora|||0000-0002-9606-0600
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:293116
Acceso en línea:https://ddd.uab.cat/record/293116
https://dx.doi.org/urn:doi:10.1093/brain/awab124
Access Level:acceso abierto
Palabra clave:PI4KA
Phosphoinositol
Inborn errors of metabolism
Hypomyelinating leukodystrophy
Spastic paraplegia
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spelling Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophyVerdura, Edgard|||0000-0003-3856-2060Rodríguez-Palmero, Agustí|||0000-0002-4141-5515Vélez-Santamaria, ValentinaPlanas-Serra, Laura|||0000-0002-2586-0897de la Calle, Irene|||0000-0002-2227-1640Raspall-Chaure, Miquel|||0000-0002-3132-3342Roubertie, AgatheBenkirane, MehdiSaettini, Francesco|||0000-0003-0767-3905Pavinato, Lisa|||0000-0002-7630-8365Mandrile, GiorgiaO'Leary, MelanieO'Heir, EmilyBarredo, EstibalizChacón, AlmudenaMichaud, Vincent|||0000-0002-5788-392XGoizet, CyrilRuiz, Montserrat|||0000-0003-0466-2653Schlüter, Agatha|||0000-0001-6732-1528Rouvet, IsabelleSala-Coromina, Júlia|||0000-0001-5116-6316Fossati, ChiaraIascone, MariaCanonico, FrancescoMarcé-Grau, Anna|||0000-0001-5762-4023de Souza, PrecillaAdams, David R.Casasnovas, Carlos|||0000-0002-7933-4681Rehm, Heidi L.Mefford, Heather C.|||0000-0001-7188-522XGonzález Gutiérrez-Solana, Luis|||0000-0003-2890-4565Brusco, Alfredo|||0000-0002-8318-7231Koenig, MichelMacaya Ruiz, Alfons|||0000-0001-7998-4185Pujol, Aurora|||0000-0002-9606-0600PI4KAPhosphoinositolInborn errors of metabolismHypomyelinating leukodystrophySpastic paraplegiaPhosphoinositides 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. Verdura et al. report a novel rare brain metabolic disorder caused by recessive mutations in PI4KA, which encodes an enzyme with a pivotal role in phosphoinositide metabolism at the cell membrane. The description of this syndrome will simplify the identification of undiagnosed cases with similar clinical features.Universitat Autònoma de Barcelona 22021-01-0120212021-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/293116https://dx.doi.org/urn:doi:10.1093/brain/awab124reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-1206Fundació la Marató de TV3 https://doi.org/10.13039/100008666 595/C/2020Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI20/00758Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CM18/00145Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 FI18/00141Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CD19/00221open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2931162026-06-06T12:50:31Z
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|||0000-0003-3856-2060
PI4KA
Phosphoinositol
Inborn errors of metabolism
Hypomyelinating leukodystrophy
Spastic paraplegia
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|||0000-0003-3856-2060
Rodríguez-Palmero, Agustí|||0000-0002-4141-5515
Vélez-Santamaria, Valentina
Planas-Serra, Laura|||0000-0002-2586-0897
de la Calle, Irene|||0000-0002-2227-1640
Raspall-Chaure, Miquel|||0000-0002-3132-3342
Roubertie, Agathe
Benkirane, Mehdi
Saettini, Francesco|||0000-0003-0767-3905
Pavinato, Lisa|||0000-0002-7630-8365
Mandrile, Giorgia
O'Leary, Melanie
O'Heir, Emily
Barredo, Estibaliz
Chacón, Almudena
Michaud, Vincent|||0000-0002-5788-392X
Goizet, Cyril
Ruiz, Montserrat|||0000-0003-0466-2653
Schlüter, Agatha|||0000-0001-6732-1528
Rouvet, Isabelle
Sala-Coromina, Júlia|||0000-0001-5116-6316
Fossati, Chiara
Iascone, Maria
Canonico, Francesco
Marcé-Grau, Anna|||0000-0001-5762-4023
de Souza, Precilla
Adams, David R.
Casasnovas, Carlos|||0000-0002-7933-4681
Rehm, Heidi L.
Mefford, Heather C.|||0000-0001-7188-522X
González Gutiérrez-Solana, Luis|||0000-0003-2890-4565
Brusco, Alfredo|||0000-0002-8318-7231
Koenig, Michel
Macaya Ruiz, Alfons|||0000-0001-7998-4185
Pujol, Aurora|||0000-0002-9606-0600
author Verdura, Edgard|||0000-0003-3856-2060
author_facet Verdura, Edgard|||0000-0003-3856-2060
Rodríguez-Palmero, Agustí|||0000-0002-4141-5515
Vélez-Santamaria, Valentina
Planas-Serra, Laura|||0000-0002-2586-0897
de la Calle, Irene|||0000-0002-2227-1640
Raspall-Chaure, Miquel|||0000-0002-3132-3342
Roubertie, Agathe
Benkirane, Mehdi
Saettini, Francesco|||0000-0003-0767-3905
Pavinato, Lisa|||0000-0002-7630-8365
Mandrile, Giorgia
O'Leary, Melanie
O'Heir, Emily
Barredo, Estibaliz
Chacón, Almudena
Michaud, Vincent|||0000-0002-5788-392X
Goizet, Cyril
Ruiz, Montserrat|||0000-0003-0466-2653
Schlüter, Agatha|||0000-0001-6732-1528
Rouvet, Isabelle
Sala-Coromina, Júlia|||0000-0001-5116-6316
Fossati, Chiara
Iascone, Maria
Canonico, Francesco
Marcé-Grau, Anna|||0000-0001-5762-4023
de Souza, Precilla
Adams, David R.
Casasnovas, Carlos|||0000-0002-7933-4681
Rehm, Heidi L.
Mefford, Heather C.|||0000-0001-7188-522X
González Gutiérrez-Solana, Luis|||0000-0003-2890-4565
Brusco, Alfredo|||0000-0002-8318-7231
Koenig, Michel
Macaya Ruiz, Alfons|||0000-0001-7998-4185
Pujol, Aurora|||0000-0002-9606-0600
author_role author
author2 Rodríguez-Palmero, Agustí|||0000-0002-4141-5515
Vélez-Santamaria, Valentina
Planas-Serra, Laura|||0000-0002-2586-0897
de la Calle, Irene|||0000-0002-2227-1640
Raspall-Chaure, Miquel|||0000-0002-3132-3342
Roubertie, Agathe
Benkirane, Mehdi
Saettini, Francesco|||0000-0003-0767-3905
Pavinato, Lisa|||0000-0002-7630-8365
Mandrile, Giorgia
O'Leary, Melanie
O'Heir, Emily
Barredo, Estibaliz
Chacón, Almudena
Michaud, Vincent|||0000-0002-5788-392X
Goizet, Cyril
Ruiz, Montserrat|||0000-0003-0466-2653
Schlüter, Agatha|||0000-0001-6732-1528
Rouvet, Isabelle
Sala-Coromina, Júlia|||0000-0001-5116-6316
Fossati, Chiara
Iascone, Maria
Canonico, Francesco
Marcé-Grau, Anna|||0000-0001-5762-4023
de Souza, Precilla
Adams, David R.
Casasnovas, Carlos|||0000-0002-7933-4681
Rehm, Heidi L.
Mefford, Heather C.|||0000-0001-7188-522X
González Gutiérrez-Solana, Luis|||0000-0003-2890-4565
Brusco, Alfredo|||0000-0002-8318-7231
Koenig, Michel
Macaya Ruiz, Alfons|||0000-0001-7998-4185
Pujol, Aurora|||0000-0002-9606-0600
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
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author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv PI4KA
Phosphoinositol
Inborn errors of metabolism
Hypomyelinating leukodystrophy
Spastic paraplegia
topic PI4KA
Phosphoinositol
Inborn errors of metabolism
Hypomyelinating leukodystrophy
Spastic paraplegia
description Phosphoinositides 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. Verdura et al. report a novel rare brain metabolic disorder caused by recessive mutations in PI4KA, which encodes an enzyme with a pivotal role in phosphoinositide metabolism at the cell membrane. The description of this syndrome will simplify the identification of undiagnosed cases with similar clinical features.
publishDate 2021
dc.date.none.fl_str_mv 2
2021-01-01
2021
2021-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/293116
https://dx.doi.org/urn:doi:10.1093/brain/awab124
url https://ddd.uab.cat/record/293116
https://dx.doi.org/urn:doi:10.1093/brain/awab124
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-1206
Fundació la Marató de TV3 https://doi.org/10.13039/100008666 595/C/2020
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI20/00758
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CM18/00145
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 FI18/00141
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CD19/00221
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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