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

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.

Publication DOI: https://doi.org/10.1093/brain/awad146
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
Funding Information: 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.
Additional Information: 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 (https://creativecommons.org/licenses/by-nc/4.0/), 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 journals.permissions@oup.com. 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.
Uncontrolled Keywords: 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,Clinical Neurology
Publication ISSN: 1460-2156
Last Modified: 14 Jun 2024 07:29
Date Deposited: 05 May 2023 17:24
Full Text Link:
Related URLs: https://academi ... awad146/7152690 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2023-08-01
Published Online Date: 2023-05-05
Accepted Date: 2023-04-14
Authors: Passchier, Emma M J
Kerst, Sven
Brouwers, Eelke
Hamilton, Eline M C
Bisseling, Quinty
Bugiani, Marianna
Waisfisz, Quinten
Kitchen, Philip (ORCID Profile 0000-0002-1558-4673)
Unger, Lucas (ORCID Profile 0000-0001-5719-7893)
Breur, Marjolein
Hoogterp, Leoni
de Vries, Sharon I
Abbink, Truus E M
Kole, Maarten H P
Leurs, Rob
Vischer, Henry F
Brignone, Maria S
Ambrosini, Elena
Feillet, François
Born, Alfred P
Epstein, Leon G
Mansvelder, Huibert D
Min, Rogier
van der Knaap, Marjo S

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