Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema

  • Brain. 2023 Aug 1;146(8):3444-3454. doi: 10.1093/brain/awad146.
Emma M J Passchier  1  2 ,  Sven Kerst  1  2 ,  Eelke Brouwers  1  2 ,  Eline M C Hamilton  1 ,  Quinty Bisseling  1  2 ,  Marianna Bugiani  3 ,  Quinten Waisfisz  4 ,  Philip Kitchen  5 ,  Lucas Unger  5 ,  Marjolein Breur  1  3 ,  Leoni Hoogterp  1 ,  Sharon I de Vries  6 ,  Truus E M Abbink  1 ,  Maarten H P Kole  6  7 ,  Rob Leurs  8 ,  Henry F Vischer  8 ,  Maria S Brignone  9 ,  Elena Ambrosini  9 ,  François Feillet  10 ,  Alfred P Born  11 ,  Leon G Epstein  12  13  14 ,  Huibert D Mansvelder  2 ,  Rogier Min  1  2 ,  Marjo S van der Knaap  1  2
Affiliations
  • 1. Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands.
  • 2. Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands.
  • 3. Department of Pathology, Amsterdam Leukodystrophy Center, Amsterdam University Medical Centers, location Vrije Universiteit Amsterdam, Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands.
  • 4. Department of Human Genetics, Amsterdam University Medical Centers location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
  • 5. School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
  • 6. Department of Axonal Signaling, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands.
  • 7. Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CC Utrecht, The Netherlands.
  • 8. Division of Medicinal Chemistry, Faculty of Science, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
  • 9. Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy.
  • 10. Reference Center for Inherited Metabolic Diseases, INSERM UMR_S 1256 NGERE, Nancy University Hospital, Vandoeuvre-lès-Nancy 54511, France.
  • 11. Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
  • 12. Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
  • 13. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 14. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
PMID: 37143309 DOI: 10.1093/brain/awad146
Abstract

Brain oedema is a life-threatening complication of various neurological conditions. Understanding molecular mechanisms of brain volume regulation is critical for therapy development. Unique insight comes from monogenic diseases characterized by chronic brain oedema, of which megalencephalic leukoencephalopathy with subcortical cysts (MLC) is the prototype. Variants in MLC1 or GLIALCAM, encoding proteins involved in astrocyte volume regulation, are the main causes of MLC. In some patients, the genetic cause remains unknown. We performed genetic studies to identify novel gene variants in MLC patients, diagnosed by clinical and MRI features, without MLC1 or GLIALCAM variants. We determined subcellular localization of the related novel proteins in cells and in human brain tissue. We investigated functional consequences of the newly identified variants on volume regulation pathways using cell volume measurements, biochemical analysis and electrophysiology. We identified a novel homozygous variant in AQP4, encoding the water channel aquaporin-4, in two siblings, and two de novo heterozygous variants in GPRC5B, encoding the orphan G protein-coupled receptor GPRC5B, in three unrelated patients. The AQP4 variant disrupts membrane localization and thereby channel function. GPRC5B, like MLC1, GlialCAM and aquaporin-4, is expressed in astrocyte endfeet in human brain. Cell volume regulation is disrupted in GPRC5B patient-derived lymphoblasts. GPRC5B functionally interacts with ion channels involved in astrocyte volume regulation. In conclusion, we identify aquaporin-4 and GPRC5B as old and new players in genetic brain oedema. Our findings shed light on the protein complex involved in astrocyte volume regulation and identify GPRC5B as novel potentially druggable target for treating brain oedema.

Keywords
GPRC5B; aquaporin-4; brain oedema; leukodystrophy; volume regulation.