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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Detalles Bibliográficos
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
Descripción
Sumario: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.

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