Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy
| Autor: | Agatha Schlüter, Cyril Goizet, Miquel Raspall-Chaure, Almudena Chacón, Mehdi Benkirane, Lisa Pavinato, Agustí Rodríguez-Palmero, Isabelle Rouvet, Irene de la Calle, Francesco Saettini, Carlos Casasnovas, Michel Koenig, Vincent Michaud, Júlia Sala-Coromina, Melanie O’Leary, Emily O'Heir, Aurora Pujol, Alfons Macaya, Chiara Fossati, Precilla de Souza, Alfredo Brusco, David R. Adams, Heather C Mefford, Luis González Gutiérrez-Solana, Valentina Vélez-Santamaría, Maria Iascone, Estibaliz Barredo, Agathe Roubertie, Francesco Canonico, Anna Marcé-Grau, Giorgia Mandrile, Edgard Verdura, Heidi L. Rehm, Montserrat Ruiz, Laura Planas-Serra |
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| Přispěvatelé: | Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Català de la Salut, [Verdura E, Planas-Serra L] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Centre for Biomedical Research in Network on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain. [Rodríguez-Palmero A] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Catalonia, Spain. [Vélez-Santamaria V] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain. [de la Calle I] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. [Raspall-Chaure M] Grup de Recerca en Neurologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2021 |
| Předmět: |
Male
Mielina - Malalties - Aspectes genètics [SDV]Life Sciences [q-bio] medicine.disease_cause 0302 clinical medicine Malalties hereditàries PI4KA hypomyelinating leukodystrophy inborn errors of metabolism phosphoinositol spastic paraplegia Child Exome 0303 health sciences Mutation Pediatria medicine.diagnostic_test AcademicSubjects/SCI01870 Otros calificadores::Otros calificadores::/genética [Otros calificadores] Malalties del sistema nerviós central Metabolic disorder Human brain Phenotype Pedigree Blot Phosphotransferases (Alcohol Group Acceptor) medicine.anatomical_structure Child Preschool Female enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebrales metabólicas::enfermedades cerebrales metabólicas congénitas::enfermedades desmielinizantes hereditarias del sistema nervioso central [ENFERMEDADES] Genetic disorders Central nervous system diseases Adult Adolescent Health Occupations::Medicine::Pediatrics [DISCIPLINES AND OCCUPATIONS] Biology Immunofluorescence Minor Histocompatibility Antigens 03 medical and health sciences Other subheadings::Other subheadings::/genetics [Other subheadings] medicine Humans profesiones sanitarias::medicina::pediatría [DISCIPLINAS Y OCUPACIONES] Alleles 030304 developmental biology trastornos mentales::trastornos del desarrollo neurológico [PSIQUIATRÍA Y PSICOLOGÍA] Leukodystrophy Infant Newborn Genetic Variation Infant Original Articles Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Brain Diseases Metabolic::Brain Diseases Metabolic Inborn::Hereditary Central Nervous System Demyelinating Diseases [DISEASES] medicine.disease Sistema nerviós - Malalties - Aspectes genètics Hereditary Central Nervous System Demyelinating Diseases Neurodevelopmental Disorders Leukocytes Mononuclear Cancer research AcademicSubjects/MED00310 Neurology (clinical) 030217 neurology & neurosurgery Mental Disorders::Neurodevelopmental Disorders [PSYCHIATRY AND PSYCHOLOGY] |
| Zdroj: | Brain r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol instname Brain-A Journal of Neurology Brain-A Journal of Neurology, Oxford University Press (OUP), 2021, ⟨10.1093/brain/awab124⟩ Dipòsit Digital de la UB Universidad de Barcelona Scientia |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awab124⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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