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
摘要
背景：兴奋性氨基酸转运蛋白2 （EAAT2）是人脑中主要的谷氨酸转运蛋白，是兴奋性神经传递的关键介质。在这里，我们提出了一个18个人的队列，其中包含13种不同的SLC1A2变异，他们都表现出不同症状和疾病严重程度的神经发育障碍，我们描述了这些变异对EAAT2功能的影响。方法：通过共聚焦显微镜、酶联免疫吸附和[3H]- d -天冬氨酸摄取测定以及电生理记录，研究了9种新型错义SLC1A2变异对哺乳动物细胞中表达的EAAT2的表达、转运和阴离子通道特性的影响。结果：13个SLC1A2变异中的10个介导EAAT2表达和/或功能的显著改变。这些分子表型分为三种类型：全面功能丧失（F249Sfs∗17,A432D, A439V, C .1421+1G>C），轻度阴离子通道获得功能（I276S, G360A）和混合运输丧失/阴离子通道获得功能（G82R, L85R, L85P, P289R）。相比之下，L37P、H542R和I546T没有介导EAAT2表达或功能的显著变化。尽管在每个类别中携带变异的个体的具体临床结果有所不同，但就表型特征和严重程度而言，这三类总体上转化为不同的临床表型。解释：观察到的这些变异产生的功能影响和临床表型之间的关联，为slc1a2相关神经发育障碍的进展和严重程度的未来预测提供了有价值的见解。此外，变异诱导的EAAT2功能变化与表型性状之间的这些关联可能有助于定制这些疾病的个性化治疗。资助：这项工作由德国教育和研究部和伦德贝克基金会资助。
The severity of SLC1A2-associated neurodevelopmental disorders correlates with transporter dysfunction.
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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