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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Detalhes bibliográficos
Autores: Verdura, Edgard, Rodríguez Palmero, Agustí, Vélez Santamaría, Valentina, Planas Serra, Laura, Calle, Irene de la, Raspall Chaure, Miquel, Roubertie, Agathe, Benkirane, Mehdi, Saettini, Francesco, Pavinato, Lisa, Mandrile, Giorgia, O’leary, Melanie, O’heir, Emily, Barredo, Estibaliz, Chacón, Almudena, Michaud, Vincent, Goizet, Cyril, Ruiz, Montserrat, Schlüter, Agatha, Rouvet, Isabelle, Sala Coromina, Júlia, Fossati, Chiara, Iascone, Maria, Canonico, Francesco, Marcé Grau, Anna, Souza, Precilla de, Adams, David, Casasnovas Pons, Carlos, Rehm, Heidi L., Mefford, Heather C., González Gutiérrez-Solana, Luis, Brusco, Alfredo, Koenig, Michel, Macaya, Alfons, Pujol, Aurora, 1968-
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/182762
Acesso em linha:https://hdl.handle.net/2445/182762
Access Level:acceso abierto
Palavra-chave:Malalties del sistema nerviós central
Malalties hereditàries
Central nervous system diseases
Genetic disorders
Descrição
Resumo: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.

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