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 Born; Leon G Epstein; Huibert D Mansvelder; Rogier Min; Marjo S van der Knaap

doi:10.1093/brain/awad146

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

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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.

Original language	English
Pages (from-to)	3444-3454
Journal	Brain
Volume	146
DOIs	https://doi.org/10.1093/brain/awad146
Publication status	Published - 05 May 2023

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Passchier, E. M. J., Kerst, S., Brouwers, E., Hamilton, E. M. C., Bisseling, Q., Bugiani, M., Waisfisz, Q., Kitchen, P., Unger, L., Breur, M., Hoogterp, L., de Vries, S. I., Abbink, T. E. M., Kole, M. H. P., Leurs, R., Vischer, H. F., Brignone, M. S., Ambrosini, E., Feillet, F., ... van der Knaap, M. S. (2023). Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema. Brain, 146, 3444-3454. https://doi.org/10.1093/brain/awad146

@article{7e5bd869d67a49e4bf8956e73ebcc661,

title = "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.",

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

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.",

year = "2023",

month = may,

day = "5",

doi = "10.1093/brain/awad146",

language = "English",

volume = "146",

pages = "3444--3454",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

}

Passchier, EMJ, Kerst, S, Brouwers, E, Hamilton, EMC, Bisseling, Q, Bugiani, M, Waisfisz, Q, Kitchen, P, Unger, L, Breur, M, Hoogterp, L, de Vries, SI, Abbink, TEM, Kole, MHP, Leurs, R, Vischer, HF, Brignone, MS, Ambrosini, E, Feillet, F, Born, AP, Epstein, LG, Mansvelder, HD, Min, R & van der Knaap, MS 2023, 'Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema', Brain, vol. 146, pp. 3444-3454. https://doi.org/10.1093/brain/awad146

TY - JOUR

T1 - Aquaporin-4 and GPRC5B

T2 - old and new players in controlling brain oedema

AU - Passchier, Emma M J

AU - Kerst, Sven

AU - Brouwers, Eelke

AU - Hamilton, Eline M C

AU - Bisseling, Quinty

AU - Bugiani, Marianna

AU - Waisfisz, Quinten

AU - Kitchen, Philip

AU - Unger, Lucas

AU - Breur, Marjolein

AU - Hoogterp, Leoni

AU - de Vries, Sharon I

AU - Abbink, Truus E M

AU - Kole, Maarten H P

AU - Leurs, Rob

AU - Vischer, Henry F

AU - Brignone, Maria S

AU - Ambrosini, Elena

AU - Feillet, François

AU - Born, Alfred P

AU - Epstein, Leon G

AU - Mansvelder, Huibert D

AU - Min, Rogier

AU - van der Knaap, Marjo S

PY - 2023/5/5

Y1 - 2023/5/5

N2 - 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.

AB - 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.

U2 - 10.1093/brain/awad146

DO - 10.1093/brain/awad146

M3 - Article

C2 - 37143309

SN - 0006-8950

VL - 146

SP - 3444

EP - 3454

JO - Brain

JF - Brain

ER -

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

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