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

Emma M J Passchier, Sven Kerst, Eelke Brouwers, Eline M C Hamilton, Quinty Bisseling, Marianna Bugiani, Quinten Waisfisz, Philip Kitchen, Lucas Unger, Marjolein Breur, Leoni Hoogterp, Sharon I de Vries, Truus E M Abbink, Maarten H P Kole, Rob Leurs, Henry F Vischer, Maria S Brignone, Elena Ambrosini, François Feillet, Alfred P BornLeon G Epstein, Huibert D Mansvelder, Rogier Min*, Marjo S van der Knaap*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)3444-3454
Number of pages11
Issue number8
Early online date5 May 2023
Publication statusPublished - 1 Aug 2023

Bibliographical note

Copyright © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License
(, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact

Funding: Supported in part by grants from ZonMW (VIDI grant 91718392) and the Dutch Rare Disease Foundation (Zeldzame Ziekten Fonds). TEMA, RM and MvdK are members of the European reference network for rare neurological disorders (ERN-RND), project ID 739510.


  • GPRC5B
  • aquaporin-4
  • brain oedema
  • leukodystrophy
  • volume regulation
  • Aquaporin 4/genetics
  • Astrocytes/metabolism
  • Mutation/genetics
  • Brain Edema/genetics
  • Humans
  • Membrane Proteins/genetics
  • Hereditary Central Nervous System Demyelinating Diseases/genetics
  • Receptors, G-Protein-Coupled/genetics
  • Brain/metabolism


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