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2021-08-20

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cc by-nc (c) Verdura, Edgard et al, 2021
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/182762

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

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https://doi.org/10.1093/brain/awab124

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.

Matèries

Malalties del sistema nerviós central, Malalties hereditàries

Matèries (anglès)

Central nervous system diseases, Genetic disorders

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Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

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. Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy. _Brain_. 2021. Vol.  vol 144, núm. num 9, pàgs. 2659-2669. [consulta: 6 de febrer de 2026]. ISSN: 1460-2156. [Disponible a: https://hdl.handle.net/2445/182762]

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