Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia.

Autor:	Nakamura Y; Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 4678601, Japan., Shimada IS; Department of Cell Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 4678601, Japan., Maroofian R; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Falabella M; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Zaki MS; Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt., Fujimoto M; Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 4678601, Japan., Sato E; Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 4678601, Japan., Takase H; Core Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya 4678601, Japan., Aoki S; Department of Pediatrics, Jichi Medical University, Tochigi 3290498, Japan., Miyauchi A; Department of Pediatrics, Jichi Medical University, Tochigi 3290498, Japan., Koshimizu E; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 2360004, Japan., Miyatake S; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 2360004, Japan.; Department of Clinical Genetics, Yokohama City University Hospital, Yokohama 2360004, Japan., Arioka Y; Pathophysiology of Mental Disorders, Nagoya University Graduate School of Medicine, Nagoya 4668550, Japan., Honda M; Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.; Laboratory of Molecular and Cellular Physiology, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 7398526, Japan., Higashi T; Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 1138655, Japan., Miya F; Center for Medical Genetics, Keio University School of Medicine, Tokyo, 1608582, Japan., Okubo Y; Department of Pediatric Neurology, Miyagi Children's Hospital, Sendai 9893126, Japan., Ogawa I; Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 4678603, Japan., Scardamaglia A; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Miryounesi M; Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1516745811, Iran., Alijanpour S; Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1516745811, Iran., Ahmadabadi F; Pediatric Neurology Department, Faculty of Medicine, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran 1546815514, Iran., Herkenrath P; Department of Pediatrics and Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany., Dafsari HS; Department of Pediatrics and Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany.; Max-Planck-Institute for Biology of Ageing, Cologne 50931, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany., Velmans C; Faculty of Medicine and University Hospital Cologne, Institute of Human Genetics, University of Cologne, Cologne 50931, Germany., Al Balwi M; Department of Pathology and Laboratory Medicine, College of Medicine, KSAU-HS, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia., Vitobello A; Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon 21000, France.; INSERM UMR1231 GAD 'Génétique des Anomalies du Développement', FHU-TRANSLAD, University of Burgundy, Dijon 21000, France., Denommé-Pichon AS; Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon 21000, France.; INSERM UMR1231 GAD 'Génétique des Anomalies du Développement', FHU-TRANSLAD, University of Burgundy, Dijon 21000, France., Jeanne M; Genetics Department, University Hospital of Tours, Tours 37044, France.; UMR 1253, iBrain, University of Tours, INSERM, Tours 37032, France., Civit A; Genetics Department, University Hospital of Tours, Tours 37044, France., Abdel-Hamid MS; Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt., Naderi H; Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan 4918936316, Iran., Darvish H; Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan 4918936316, Iran., Bakhtiari S; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, AZ 85004, USA., Kruer MC; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.; Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, AZ 85004, USA., Carroll CJ; Genetics Section, Molecular and Clinical Sciences Research Institute, St. George's, University of London, London SW17 0RE, UK., Ghayoor Karimiani E; Genetics Section, Molecular and Clinical Sciences Research Institute, St. George's, University of London, London SW17 0RE, UK., Khailany RA; Department of Basic Science, Hawler Medical University, Erbil, Kurdistan Region 44001, Iraq., Abdulqadir TA; Department of Pediatrics, College of Medicine, Hawler Medical University, Erbil, Kurdistan Region 44001, Iraq., Ozaslan M; Department of Biology, Division of Molecular Biology and Genetics, Gaziantep University, Gaziantep 27410, Turkey., Bauer P; Centogene GmbH, Rostock 18055, Germany., Zifarelli G; Centogene GmbH, Rostock 18055, Germany., Seifi T; Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz 83151-61355, Iran.; Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz 61556-89467, Iran., Zamani M; Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz 83151-61355, Iran.; Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz 61556-89467, Iran., Al Alam C; Pediatrics and Pediatric Neurology, American Center for Psychiatry and Neurology, Abu Dhabi 108699, UAE., Alvi JR; Department of Pediatric Neurology, the Children's Hospital and the University of Child Health Sciences, Lahore 54600, Pakistan., Sultan T; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Efthymiou S; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Pope SAS; Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.; Neurometabolic Unit, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK., Haginoya K; Department of Pediatric Neurology, Miyagi Children's Hospital, Sendai 9893126, Japan., Matsunaga T; Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 4678603, Japan., Osaka H; Department of Pediatrics, Jichi Medical University, Tochigi 3290498, Japan., Matsumoto N; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 2360004, Japan., Ozaki N; Pathophysiology of Mental Disorders, Nagoya University Graduate School of Medicine, Nagoya 4668550, Japan., Ohkawa Y; Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 8128582, Japan., Oki S; Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan.; Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 8600811, Japan., Tsunoda T; Laboratory for Medical Science Mathematics, Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo 113-0033, Japan.; Laboratory for Medical Science Mathematics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 113-0033, Japan.; Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan., Pitceathly RDS; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK., Taketomi Y; Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 1138655, Japan., Houlden H; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK., Murakami M; Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 1138655, Japan., Kato Y; Department of Cell Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 4678601, Japan., Saitoh S; Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 4678601, Japan.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Nov 04; Vol. 147 (11), pp. 3949-3967.
DOI:	10.1093/brain/awae185
Abstrakt:	Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu