{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:06:35Z","timestamp":1788941195584,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY028580"],"award-info":[{"award-number":["EY028580"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["40\u201000812\u201098\u201011005"],"award-info":[{"award-number":["40\u201000812\u201098\u201011005"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["91718392"],"award-info":[{"award-number":["91718392"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SLC4A4<\/jats:italic>\n                      encodes electrogenic sodium bicarbonate cotransporter NBCe1, prominently expressed in kidney and brain. Recessive loss\u2010of\u2010function variants in\n                      <jats:italic>SLC4A4<\/jats:italic>\n                      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\n                      <jats:italic>SLC4A4<\/jats:italic>\n                      in patients with brain edema and investigate how it affects NBCe1 function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The same heterozygous variant in\n                      <jats:italic>SLC4A4<\/jats:italic>\n                      was found in all three patients and one parent. The children displayed infantile\u2010onset 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      The most likely pathomechanism of this novel\n                      <jats:italic>SLC4A4<\/jats:italic>\n                      \u2010related 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70363","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:37:40Z","timestamp":1773758260000},"page":"1817-1830","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Depolarizing Leak in Sodium Bicarbonate Cotransporter\n                    <scp>NBCe1<\/scp>\n                    Causes Brain Edema"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4843-2139","authenticated-orcid":false,"given":"Quinty","family":"Bisseling","sequence":"first","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital Amsterdam University Medical Center, Amsterdam Neuroscience  Amsterdam the Netherlands"},{"name":"Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research Vrije Universiteit Amsterdam, Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark D.","family":"Parker","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences The State University of New York: The University at Buffalo  Buffalo New York USA"},{"name":"Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences The State University of New York: The University at Buffalo  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Kerst","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital Amsterdam University Medical Center, Amsterdam Neuroscience  Amsterdam the Netherlands"},{"name":"Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research Vrije Universiteit Amsterdam, Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Pasternack","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences The State University of New York: The University at Buffalo  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Tondreau","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences The State University of New York: The University at Buffalo  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolein","family":"Breur","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital Amsterdam University Medical Center, Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma M.","family":"van Rooijen\u2010van Leeuwen","sequence":"additional","affiliation":[{"name":"Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital Amsterdam University Medical Center, Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Tonduti","sequence":"additional","affiliation":[{"name":"Unit of Pediatric Neurology, C.O.A.L.A (Center for Diagnosis and Treatment of Leukodystrophies) Vittore Buzzi Children's Hospital  Milan Italy"},{"name":"Department of Biomedical and Clinical Sciences Universit\u00e0 Degli Studi di Milano  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9167-1878","authenticated-orcid":false,"given":"Ettore","family":"Salsano","sequence":"additional","affiliation":[{"name":"Unit of Rare Neurological Diseases Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Darling","sequence":"additional","affiliation":[{"name":"Neurometabolic Unit, Movement Disorders Unit, Neurology Department Hospital Sant Joan de D\u00e9u  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna A. 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