A Depolarizing Leak in Sodium Bicarbonate Cotransporter NBCe1 Causes Brain Edema
(2026) In Annals of Clinical and Translational Neurology- Abstract
Objectives: SLC4A4 encodes electrogenic sodium bicarbonate cotransporter NBCe1, prominently expressed in kidney and brain. Recessive loss-of-function variants in SLC4A4 cause proximal renal tubular acidosis, no brain edema. In the brain, NBCe1 is expressed by astrocytes, where it regulates pH and mediates astrocyte volume changes. Here we describe a novel dominant variant in SLC4A4 in patients with brain edema and investigate how it affects NBCe1 function. Methods: Genetic studies identified a novel gene variant in three unrelated pediatric patients with the same MRI pattern of cerebral subcortical white matter signal abnormality and swelling, and medulla lesions. Immunohistochemical and electrophysiological experiments were performed... (More)
Objectives: SLC4A4 encodes electrogenic sodium bicarbonate cotransporter NBCe1, prominently expressed in kidney and brain. Recessive loss-of-function variants in SLC4A4 cause proximal renal tubular acidosis, no brain edema. In the brain, NBCe1 is expressed by astrocytes, where it regulates pH and mediates astrocyte volume changes. Here we describe a novel dominant variant in SLC4A4 in patients with brain edema and investigate how it affects NBCe1 function. Methods: Genetic studies identified a novel gene variant in three unrelated pediatric patients with the same MRI pattern of cerebral subcortical white matter signal abnormality and swelling, and medulla lesions. Immunohistochemical and electrophysiological experiments were performed to determine the localization of the transporter in the brain and the functional consequence of the patient variant. Results: The same heterozygous variant in SLC4A4 was found in all three patients and one parent. The children displayed infantile-onset progressive macrocephaly, motor and cognitive impairment, autism, epilepsy, and recurrent episodes of increased intracranial pressure. Bicarbonate treatment of two patients led to clinical and MRI improvement. Immunohistochemistry revealed that brain NBCe1 is mainly present in astrocytes, more in cortex than white matter. Functional experiments revealed impaired transporter activity of mutant NBCe1 due to reduced membrane expression and a prominent depolarizing ion leak. Interpretation: The most likely pathomechanism of this novel SLC4A4-related disease is that a depolarizing leak in NBCe1 disrupts astrocyte pH regulation, promoting swelling and impairing volume control. These findings uncover a previously unrecognized mechanism of genetic brain edema and establish NBCe1 as a critical modulator of astrocyte homeostasis.
(Less)
- author
- organization
- publishing date
- 2026
- type
- Contribution to journal
- publication status
- in press
- subject
- keywords
- astrocyte, brain edema, leukodystrophy, NBCe1, renal tubular acidosis, SLC4A4
- in
- Annals of Clinical and Translational Neurology
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- scopus:105033263374
- pmid:41841191
- ISSN
- 2328-9503
- DOI
- 10.1002/acn3.70363
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2026 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
- id
- 0ba3f856-2e70-418a-b414-1e66b5095748
- date added to LUP
- 2026-05-19 15:01:33
- date last changed
- 2026-06-02 16:03:50
@article{0ba3f856-2e70-418a-b414-1e66b5095748,
abstract = {{<p>Objectives: SLC4A4 encodes electrogenic sodium bicarbonate cotransporter NBCe1, prominently expressed in kidney and brain. Recessive loss-of-function variants in SLC4A4 cause proximal renal tubular acidosis, no brain edema. In the brain, NBCe1 is expressed by astrocytes, where it regulates pH and mediates astrocyte volume changes. Here we describe a novel dominant variant in SLC4A4 in patients with brain edema and investigate how it affects NBCe1 function. Methods: Genetic studies identified a novel gene variant in three unrelated pediatric patients with the same MRI pattern of cerebral subcortical white matter signal abnormality and swelling, and medulla lesions. Immunohistochemical and electrophysiological experiments were performed to determine the localization of the transporter in the brain and the functional consequence of the patient variant. Results: The same heterozygous variant in SLC4A4 was found in all three patients and one parent. The children displayed infantile-onset progressive macrocephaly, motor and cognitive impairment, autism, epilepsy, and recurrent episodes of increased intracranial pressure. Bicarbonate treatment of two patients led to clinical and MRI improvement. Immunohistochemistry revealed that brain NBCe1 is mainly present in astrocytes, more in cortex than white matter. Functional experiments revealed impaired transporter activity of mutant NBCe1 due to reduced membrane expression and a prominent depolarizing ion leak. Interpretation: The most likely pathomechanism of this novel SLC4A4-related disease is that a depolarizing leak in NBCe1 disrupts astrocyte pH regulation, promoting swelling and impairing volume control. These findings uncover a previously unrecognized mechanism of genetic brain edema and establish NBCe1 as a critical modulator of astrocyte homeostasis.</p>}},
author = {{Bisseling, Quinty and Parker, Mark D. and Kerst, Sven and Pasternack, Richard A. and Tondreau, Jacob and Breur, Marjolein and van Rooijen-van Leeuwen, Gemma M. and Tonduti, Davide and Salsano, Ettore and Darling, Alejandra and van Wijk, Joanna A.E. and Törnroth-Horsefield, Susanna and Bugiani, Marianna and Pouwels, Petra J.W. and Waisfisz, Quinten and van der Knaap, Marjo S. and Min, Rogier}},
issn = {{2328-9503}},
keywords = {{astrocyte; brain edema; leukodystrophy; NBCe1; renal tubular acidosis; SLC4A4}},
language = {{eng}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Annals of Clinical and Translational Neurology}},
title = {{A Depolarizing Leak in Sodium Bicarbonate Cotransporter NBCe1 Causes Brain Edema}},
url = {{http://dx.doi.org/10.1002/acn3.70363}},
doi = {{10.1002/acn3.70363}},
year = {{2026}},
}