Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
Verdura, Edgard (Instituto de Salud Carlos III)
Rodríguez-Palmero, Agustí (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Vélez-Santamaria, Valentina (Hospital Universitari de Bellvitge)
Planas-Serra, Laura (Instituto de Salud Carlos III)
de la Calle, Irene (Institut d'Investigació Biomèdica de Bellvitge)
Raspall-Chaure, Miquel (Hospital Universitari Vall d'Hebron)
Roubertie, Agathe (Institut des Neurosciences de Montpellier)
Benkirane, Mehdi (Université de Montpellier)
Saettini, Francesco (Paediatric Hematology Department, University of Milano Bicocca)
Pavinato, Lisa (Department of Medical Sciences, University of Torino)
Mandrile, Giorgia (San Luigi Gonzaga University Hospital (Orbassano, Itàlia))
O'Leary, Melanie (Broad Institute of MIT and Harvard (Cambridge, Estats Units d'Amèrica))
O'Heir, Emily (Broad Institute of MIT and Harvard (Cambridge, Estats Units d'Amèrica))
Barredo, Estibaliz (Hospital General Universitario Gregorio Marañón)
Chacón, Almudena (Hospital General Universitario Gregorio Marañón)
Michaud, Vincent (University of Bordeaux (França))
Goizet, Cyril (University Hospital Centre Bordeaux Pellegrin Hospital Group)
Ruiz, Montserrat (Instituto de Salud Carlos III)
Schlüter, Agatha (Instituto de Salud Carlos III)
Rouvet, Isabelle (Hospices Civils de Lyon)
Sala-Coromina, Júlia (Hospital Universitari Vall d'Hebron)
Fossati, Chiara (Fondazione MBBM (Monza, Itàlia))
Iascone, Maria (Papa Giovanni XXIII Hospital (Bèrgam, Itàlia))
Canonico, Francesco (Department of Neuroradiology, University of Milan-Bicocca)
Marcé-Grau, Anna (Vall d'Hebron Institut de Recerca (VHIR))
de Souza, Precilla (National Human Genome Research Institute (Bethesda, Estats Units d'Amèrica))
Adams, David R. (Undiagnosed Diseases Program, The Common Fund (Bethesda, Estats Units d'Amèrica))
Casasnovas, Carlos (Hospital Universitari de Bellvitge)
Rehm, Heidi L. (Broad Institute of MIT and Harvard (Cambridge, Estats Units d'Amèrica))
Mefford, Heather C. (University of Washington)
González Gutiérrez-Solana, Luis (Hospital Infantil Universitario Niño Jesús (Madrid))
Brusco, Alfredo (University of Torino)
Koenig, Michel (Université de Montpellier)
Macaya Ruiz, Alfons (Vall d'Hebron Institut de Recerca (VHIR))
Pujol, Aurora 1968- (Institució Catalana de Recerca i Estudis Avançats)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	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.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1206 Fundació la Marató de TV3 595/C/2020 Instituto de Salud Carlos III PI20/00758 Instituto de Salud Carlos III CM18/00145 Instituto de Salud Carlos III FI18/00141 Instituto de Salud Carlos III CD19/00221
Drets:	Aquest 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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	PI4KA ; Phosphoinositol ; Inborn errors of metabolism ; Hypomyelinating leukodystrophy ; Spastic paraplegia
Publicat a:	Brain, Vol. 144 (august 2021) , p. 2659-2669, ISSN 1460-2156

DOI: 10.1093/brain/awab124
PMID: 34415322

11 p, 1.4 MB

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