Peter Kovermann, Allan Bayat, Christina D Fenger, Lisette Leeuwen, Artem Borovikov, Artem Sharkov, Virginie Levrat, Gaetan Lesca, Laurence Perrin, Jonathan Levy, Christoph Fahlke, Rikke S Møller, Anders A Jensen
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引用次数: 0
Abstract
Background: Excitatory amino acid transporter 2 (EAAT2) is the predominant glutamate transporter and a key mediator of excitatory neurotransmission in the human brain. Here we present a cohort of 18 individuals harbouring 13 different SLC1A2 variants, who all present with neurodevelopmental impairment with variable symptoms and disease severities, and we delineate the impact of these variants on EAAT2 function.
Methods: The consequences of nine novel missense SLC1A2 variants for expression, transport and anion channel properties of EAAT2 expressed in mammalian cells were characterized by confocal microscopy, enzyme-linked immunosorbent and [3H]-D-aspartate uptake assays, and electrophysiological recordings.
Findings: Ten of the 13 SLC1A2 variants mediated significant changes to EAAT2 expression and/or function. These molecular phenotypes were classified into three categories: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function. Although specific clinical outcomes in individuals carrying variants within each category varied somewhat, the three categories overall translated into distinct clinical phenotypes in terms of phenotypic traits and severity.
Interpretation: The observed associations between functional effects and clinical phenotypes produced by these variants offer valuable insights for future predictions of progression and severity of SLC1A2-associated neurodevelopmental disorders. Furthermore, these associations between variant-induced changes in EAAT2 function and phenotypic traits could assist in tailoring personalized treatments of these disorders.
Funding: This work was funded by the German Ministry of Education and Research and by the Lundbeck Foundation.
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍：
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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