Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy-Reference-Cited by-同舟云学术

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Published:2021-08-20 Issue:9 Volume:144 Page:2659-2669
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Verdura Edgard¹²,Rodríguez-Palmero Agustí¹³,Vélez-Santamaria Valentina¹⁴,Planas-Serra Laura¹²,de la Calle Irene¹,Raspall-Chaure Miquel⁵⁶^ORCID,Roubertie Agathe⁷⁸,Benkirane Mehdi⁹,Saettini Francesco¹⁰^ORCID,Pavinato Lisa¹¹^ORCID,Mandrile Giorgia¹²,O’Leary Melanie¹³,O’Heir Emily¹³,Barredo Estibaliz¹⁴,Chacón Almudena¹⁴,Michaud Vincent¹⁵¹⁶^ORCID,Goizet Cyril¹⁶¹⁷,Ruiz Montserrat¹²,Schlüter Agatha¹²,Rouvet Isabelle¹⁸,Sala-Coromina Julia⁵⁶,Fossati Chiara¹⁹,Iascone Maria²⁰^ORCID,Canonico Francesco²¹,Marcé-Grau Anna⁵,de Souza Precilla²²,Adams David R²²²³,Casasnovas Carlos¹²⁴,Rehm Heidi L¹³,Mefford Heather C²⁴^ORCID,González Gutierrez-Solana Luis²²⁵,Brusco Alfredo¹¹²⁶^ORCID,Koenig Michel⁹,Macaya Alfons⁵⁶,Pujol Aurora¹²²⁷

Affiliation:

1. Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain

2. Centre for Biomedical Research in Network on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain

3. Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Catalonia, Spain

4. Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain

5. Neurology Research Group, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

6. Department of Paediatric Neurology, Vall d’Hebron University Hospital, Barcelona, Spain

7. Département de Neuropédiatrie, Hôpital Gui de Chauliac Pôle Neurosciences Tête et Cou, Montpellier, France

8. INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France

9. Laboratoire de Génétique de Maladies Rares EA7402, Institut Universitaire de Recherche Clinique, Université de Montpellier, CHU Montpellier, CEDEX 5, 34295 Montpellier, France

10. Paediatric Hematology Department, Fondazione MBBM, University of Milano Bicocca, Monza, Italy

11. Department of Medical Sciences, University of Torino, 10126 Torino, Italy

12. Thalassemia Centre and Medical Genetics Unit, San Luigi Gonzaga University Hospital, Orbassano, Italy

13. Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

14. Neuropediatric Department, Hospital Universitario Gregorio Marañón, Madrid, Spain

15. Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, Aquitaine, France

16. INSERM U1211, Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Talence, Aquitaine, France

17. Reference Center for Rare Neurogenetic Diseases, Department of Medical Genetics, University Hospital Centre Bordeaux Pellegrin Hospital Group, Bordeaux, Aquitaine, France

18. Cellular Biotechnology Department and Biobank, Hospices Civils de Lyon, CHU de Lyon, Lyon, France

19. Department of Paediatrics, Fondazione MBBM, Monza, Italy

20. Molecular Genetics Laboratory, USSD LGM, Papa Giovanni XXIII Hospital, Bergamo, Italy

21. Department of Neuroradiology, University of Milan-Bicocca, San Gerardo Hospital, ASST di Monza, Monza, Italy

22. Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA

23. Undiagnosed Diseases Program, The Common Fund, NIH, Bethesda, MD, USA

24. Division of Genetic Medicine, Department of Paediatrics, University of Washington, Seattle, WA 98195, USA

25. Pediatric Neurology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain

26. Medical Genetics Unit, Città della Salute e della Scienza, University Hospital, 10126 Turin, Italy

27. Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain

Abstract

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.

Funder

Hesperia Foundation

Asociación Española contra las Leucodistrofias

Autonomous Government of Catalonia

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

Link

http://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awab124/39835313/awab124.pdf

Reference42 articles.

1. Structural basis for regulation of phosphoinositide kinases and their involvement in human disease;Burke;Mol Cell,2018