Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Edgard Verdura , Agustí Rodríguez-Palmero , Valentina Vélez-Santamaria , Laura Planas-Serra , Irene de La Calle , Miquel Raspall-Chaure , Agathe Roubertie , Mehdi Benkirane (1, 2) , Francesco Saettini , Lisa Pavinato , Giorgia Mandrile , Melanie O’leary , Emily O’heir , Estibaliz Barredo , Almudena Chacón , Vincent Michaud , Cyril Goizet , Montserrat Ruiz , Agatha Schlüter , Isabelle Rouvet , Julia Sala-Coromina , Chiara Fossati , Maria Iascone , Francesco Canonico , Anna Marcé-Grau , Precilla de Souza , David Adams , Carlos Casasnovas , Heidi Rehm , Heather Mefford , Luis González Gutierrez-Solana , Alfredo Brusco , Michel Koenig (1, 2) , Alfons Macaya , Aurora Pujol

1 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
2 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]

Abstract 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.

Domaines: Sciences du Vivant [q-bio]

Edgard Verdura, Agustí Rodríguez-Palmero, Valentina Vélez-Santamaria, Laura Planas-Serra, Irene de La Calle, et al.. Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy. Brain - A Journal of Neurology , 2021, ⟨10.1093/brain/awab124⟩. ⟨hal-03327833⟩