ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy

Author:

Mattison Kari A12ORCID,Tossing Gilles3,Mulroe Fred4,Simmons Callum4,Butler Kameryn M25,Schreiber Alison6,Alsadah Adnan6,Neilson Derek E78,Naess Karin910,Wedell Anna911,Wredenberg Anna910,Sorlin Arthur12,McCann Emma13,Burghel George J14,Menendez Beatriz15,Hoganson George E16,Botto Lorenzo D17,Filloux Francis M18,Aledo-Serrano Ángel19,Gil-Nagel Antonio19,Tatton-Brown Katrina20,Verbeek Nienke E21,van der Zwaag Bert21,Aleck Kyrieckos A78,Fazenbaker Andrew C8,Balciuniene Jorune2223,Dubbs Holly A24,Marsh Eric D24,Garber Kathryn2,Ek Jakob25,Duno Morten25,Hoei-Hansen Christina E2627,Deardorff Matthew A282930,Raca Gordana2830,Quindipan Catherine31,van Hirtum-Das Michele2930,Breckpot Jeroen32,Hammer Trine Bjørg33,Møller Rikke S3334,Whitney Andrea35,Douglas Andrew G L3637,Kharbanda Mira37,Brunetti-Pierri Nicola3839ORCID,Morleo Manuela3840,Nigro Vincenzo3840ORCID,May Halie J41,Tao James X42,Argilli Emanuela4344,Sherr Elliot H4344,Dobyns William B45ORCID,Baines Richard A4ORCID,Warwicker Jim46,Parker J Alex3,Banka Siddharth47ORCID,Campeau Philippe M48ORCID,Escayg Andrew2ORCID,

Affiliation:

1. Genetics and Molecular Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University , Atlanta, GA , USA

2. Department of Human Genetics, Emory University , Atlanta, GA , USA

3. Department of Neuroscience, University of Montreal , Montreal, QC , Canada

4. Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Center , Manchester , UK

5. Greenwood Genetics Center , Greenwood, SC , USA

6. Center for Personalized Genetic Healthcare, Cleveland Clinic , Cleveland, OH , USA

7. Division of Genetics and Metabolism, Department of Child Health, The University of Arizona College of Medicine , Phoenix, AZ , USA

8. Department of Genetics and Metabolism, Phoenix Children’s Hospital, Phoenix Children’s Medical Group , Phoenix, AZ , USA

9. Center for Inherited Metabolic Diseases, Karolinska University Hospital , Stockholm , Sweden

10. Department of Medical Biochemistry and Biophysics, Karolinska Institute , Stockholm , Sweden

11. Deparment of Molecular Medicine and Surgery, Karolinska Institute , Stockholm , Sweden

12. National Center of Genetics, Laboratoire National de Santé , Dudelange , Luxembourg

13. Liverpool Center for Genomic Medicine, Liverpool Women’s Hospital , Liverpool , UK

14. Genomic Diagnostic Laboratory, St. Mary’s Hospital, Manchester University NHS Foundation Trust , Manchester , UK

15. UI Health , Chicago, IL , USA

16. Division of Genetics, Department of Pediatrics, University of Illinois College of Medicine , Chicago, IL , USA

17. Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine , Salt Lake City, UT , USA

18. Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine , Salt Lake City, UT , USA

19. Genetic Epilepsy Program, Department of Neurology, Ruber International Hospital , Madrid , Spain

20. Medical Genetics, St. George’s University Hospitals NHS Foundation Trust and Institute for Molecular and Cell Sciences, St. George’s, University of London , London , UK

21. Department of Genetics, University Medical Center Utrecht, Member of the ERN EpiCARE , Utrecht , The Netherlands

22. Divison of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia , Philadelphia, PA , USA

23. PerkinElmer Genomics , Pittsburgh, PA , USA

24. Division of Neurology, Children’s Hospital of Philadelphia , Philadelphia, PA , USA

25. Department of Clinical Genetics, University Hospital of Copenhagen , Copenhagen , Denmark

26. Department of Pediatrics, University Hospital of Copenhagen , Copenhagen , Denmark

27. Department of Clinical Medicine, University of Copenhagen , Copenhagen , Denmark

28. Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles , Los Angeles, CA , USA

29. Department of Pediatrics, Division of Medical Genetics, Children’s Hospital Los Angeles , Los Angeles, CA , USA

30. Keck School of Medicine, University of Southern California , Los Angeles, CA , USA

31. Center for Personalized Medicine, Children’s Hospital Los Angeles , Los Angeles, CA , USA

32. Center for Human Genetics, University Hospitals Leuven , Leuven , Belgium

33. Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center , Fildelfia, Dianalund , Denmark

34. Insititue for Regional Health Services Research, University of Southern Denmark , Odense , Denmark

35. Pediatric Neurology, University Hospital Southampton NHS Foundation Trust , Southampton , UK

36. Wessex Clinical Genetics Service, University of Southampton , Southampton , UK

37. Human Development and Health, Faculty of Medicine, University of Southampton , Southampton , UK

38. Telethon Institute of Genetics and Medicine (TIGEM) , Pozzuoli , Italy

39. Department of Translational Medicine, Federico II University of Naples , Naples , Italy

40. Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’ , Naples , Italy

41. Institute for Genomic Medicine, Columbia University Irving Medical Center , New York, NY , USA

42. Department of Neurology, University of Chicago , Chicago, IL , USA

43. Department of Neurology, University of California , San Francisco, San Francisco, CA , USA

44. Pediatrics Institute of Human Genetics and Weill Institute for Neurosciences, University of California , San Francisco, San Francisco, CA , USA

45. Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota , Minneapolis, MN , USA

46. School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Institute of Biotechnology, University of Manchester , Manchester , UK

47. Division of Evolution, Infection, and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester , Manchester , UK

48. Department of Pediatrics, University of Montreal , Montreal, QC , Canada

Abstract

Abstract The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Funder

a senior clinical investigator fellowship of the FWO-Flanders

Winship Cancer Institute of Emory University

Citizens United for Research in Epilepsy

National Human Genome Research Institute

National Heart, Lung and Blood Institute

National Institutes of Health

European Union

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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