Biallelic null variants in <i>PNPLA8</i> cause microcephaly by reducing the number of basal radial glia-Reference-Cited by-同舟云学术

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

Published:2024-07-31 Issue: Volume: Page:
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Nakamura Yuji¹^ORCID,Shimada Issei S²^ORCID,Maroofian Reza³^ORCID,Falabella Micol³^ORCID,Zaki Maha S⁴,Fujimoto Masanori¹,Sato Emi¹,Takase Hiroshi⁵,Aoki Shiho⁶,Miyauchi Akihiko⁶,Koshimizu Eriko⁷,Miyatake Satoko⁷⁸^ORCID,Arioka Yuko⁹,Honda Mizuki¹⁰¹¹,Higashi Takayoshi¹²,Miya Fuyuki¹³,Okubo Yukimune¹⁴,Ogawa Isamu¹⁵,Scardamaglia Annarita³,Miryounesi Mohammad¹⁶,Alijanpour Sahar¹⁶,Ahmadabadi Farzad¹⁷,Herkenrath Peter¹⁸,Dafsari Hormos Salimi¹⁸¹⁹²⁰^ORCID,Velmans Clara²¹,Al Balwi Mohammed²²,Vitobello Antonio²³²⁴^ORCID,Denommé-Pichon Anne-Sophie²³²⁴^ORCID,Jeanne Médéric²⁵²⁶,Civit Antoine²⁵,Abdel-Hamid Mohamed S²⁷,Naderi Hamed²⁸,Darvish Hossein²⁸,Bakhtiari Somayeh²⁹³⁰,Kruer Michael C²⁹³⁰,Carroll Christopher J³¹^ORCID,Ghayoor Karimiani Ehsan³¹,Khailany Rozhgar A³²,Abdulqadir Talib Adil³³,Ozaslan Mehmet³⁴,Bauer Peter³⁵,Zifarelli Giovanni³⁵,Seifi Tahere³⁶³⁷,Zamani Mina³⁶³⁷,Al Alam Chadi³⁸,Alvi Javeria Raza³⁹,Sultan Tipu³,Efthymiou Stephanie³^ORCID,Pope Simon A S⁴⁰⁴¹,Haginoya Kazuhiro¹⁴,Matsunaga Tamihide¹⁵,Osaka Hitoshi⁶^ORCID,Matsumoto Naomichi⁷^ORCID,Ozaki Norio⁹^ORCID,Ohkawa Yasuyuki⁴²^ORCID,Oki Shinya¹⁰⁴³^ORCID,Tsunoda Tatsuhiko⁴⁴⁴⁵⁴⁶^ORCID,Pitceathly Robert D S³⁴⁷^ORCID,Taketomi Yoshitaka¹²,Houlden Henry³^ORCID,Murakami Makoto¹²,Kato Yoichi²^ORCID,Saitoh Shinji¹^ORCID

Affiliation:

1. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences , Nagoya 4678601 , Japan

2. Department of Cell Biology, Nagoya City University Graduate School of Medical Sciences , Nagoya 4678601 , Japan

3. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG , UK

4. Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre , Cairo 12622 , Egypt

5. Core Laboratory, Nagoya City University Graduate School of Medical Sciences , Nagoya 4678601 , Japan

6. Department of Pediatrics, Jichi Medical University , Tochigi 3290498 , Japan

7. Department of Human Genetics, Yokohama City University Graduate School of Medicine , Yokohama 2360004 , Japan

8. Department of Clinical Genetics, Yokohama City University Hospital , Yokohama 2360004 , Japan

9. Pathophysiology of Mental Disorders, Nagoya University Graduate School of Medicine , Nagoya 4668550 , Japan

10. Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine , Kyoto 6068507 , Japan

11. Laboratory of Molecular and Cellular Physiology, Graduate School of Integrated Sciences for Life, Hiroshima University , Hiroshima 7398526 , Japan

12. 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

13. Center for Medical Genetics, Keio University School of Medicine , Tokyo, 1608582 , Japan

14. Department of Pediatric Neurology, Miyagi Children's Hospital , Sendai 9893126 , Japan

15. Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University , Nagoya 4678603 , Japan

16. Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences , Tehran 1516745811 , Iran

17. Pediatric Neurology Department, Faculty of Medicine, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences , Tehran 1546815514 , Iran

18. Department of Pediatrics and Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne , Cologne 50937 , Germany

19. Max-Planck-Institute for Biology of Ageing , Cologne 50931 , Germany

20. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne , Cologne 50931 , Germany

21. Faculty of Medicine and University Hospital Cologne, Institute of Human Genetics, University of Cologne , Cologne 50931 , Germany

22. Department of Pathology and Laboratory Medicine, College of Medicine, KSAU-HS, Ministry of National Guard Health Affairs , Riyadh 11426 , Saudi Arabia

23. Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital , Dijon 21000 , France

24. INSERM UMR1231 GAD ‘Génétique des Anomalies du Développement’, FHU-TRANSLAD, University of Burgundy , Dijon 21000 , France

25. Genetics Department, University Hospital of Tours , Tours 37044 , France

26. UMR 1253, iBrain, University of Tours, INSERM , Tours 37032 , France

27. Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre , Cairo 12622 , Egypt

28. Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences , Gorgan 4918936316 , Iran

29. Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital , Phoenix, AZ 85016 , USA

30. Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine , Phoenix, AZ 85004 , USA

31. Genetics Section, Molecular and Clinical Sciences Research Institute, St. George's, University of London , London SW17 0RE , UK

32. Department of Basic Science, Hawler Medical University , Erbil, Kurdistan Region 44001 , Iraq

33. Department of Pediatrics, College of Medicine, Hawler Medical University , Erbil, Kurdistan Region 44001 , Iraq

34. Department of Biology, Division of Molecular Biology and Genetics, Gaziantep University , Gaziantep 27410 , Turkey

35. Centogene GmbH , Rostock 18055 , Germany

36. Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz , Ahvaz 83151-61355 , Iran

37. Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars , Ahvaz 61556-89467 , Iran

38. Pediatrics and Pediatric Neurology, American Center for Psychiatry and Neurology , Abu Dhabi 108699 , UAE

39. Department of Pediatric Neurology, the Children’s Hospital and the University of Child Health Sciences , Lahore 54600 , Pakistan

40. Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health , London WC1N 1EH , UK

41. Neurometabolic Unit, The National Hospital for Neurology and Neurosurgery , London WC1N 3BG , UK

42. Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University , Fukuoka 8128582 , Japan

43. Institute of Resource Development and Analysis, Kumamoto University , Kumamoto 8600811 , Japan

44. Laboratory for Medical Science Mathematics, Department of Biological Sciences, School of Science, The University of Tokyo , Tokyo 113-0033 , Japan

45. 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

46. Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences , Yokohama 230-0045 , Japan

47. 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

Abstract

Abstract 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.

Funder

Japan Society for the Promotion of Science

Kawano Masanori Memorial Public Interest Incorporated Foundation

Ono Medical Research Foundation

Cologne Clinician Scientist Program/Faculty of Medicine/University of Cologne

German Research Foundation

Medical Research Council

CURE

Publisher

Oxford University Press (OUP)

Link

https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awae185/58700169/awae185.pdf

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