与 GABRB2 功能增益和缺失变异相关的不同神经发育和癫痫表型。

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2024-08-01 Epub Date: 2024-07-11 DOI:10.1016/j.ebiom.2024.105236

Nazanin Azarinejad Mohammadi, Philip Kiær Ahring, Vivian Wan Yu Liao, Han Chow Chua, Sebastián Ortiz de la Rosa, Katrine Marie Johannesen, Yael Michaeli-Yossef, Aline Vincent-Devulder, Catherine Meridda, Ange-Line Bruel, Alessandra Rossi, Chirag Patel, Joerg Klepper, Paolo Bonanni, Sara Minghetti, Marina Trivisano, Nicola Specchio, David Amor, Stéphane Auvin, Sarah Baer, Pierre Meyer, Mathieu Milh, Vincenzo Salpietro, Reza Maroofian, Johannes R Lemke, Sarah Weckhuysen, Palle Christophersen, Guido Rubboli, Mary Chebib, Anders A Jensen, Nathan L Absalom, Rikke Steensbjerre Møller

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引用次数: 0

摘要

背景：GABRB2编码γ-氨基丁酸A型（GABAA）受体的β2亚基，其变异可导致多种疾病，从发热性癫痫发作到严重的发育性和癫痫性脑病。然而，轻度与重度疾病的发病风险机制仍不清楚。在这项研究中，我们对一组具有 GABRB2 变异的个体进行了全面的基因型与表型相关性分析：方法：收集了 42 名携带 26 种不同 GABRB2 变体的个体的遗传和临床电学数据，并对变体对受体功能的影响进行了电生理分析：结果：对α1β2γ2受体的电生理评估显示，25/26个变异体导致受体核心特性（如GABA敏感性）功能障碍。其中，17 个变异导致功能增益 (GOF)，8 个变异导致功能缺失 (LOF)。基因型-表型相关性分析表明，携带 GOF 变异的个体患有严重的发育迟缓/智力障碍（DD/ID，74%）、运动障碍（如肌张力障碍或运动障碍，59%）、小头畸形（50%）和早期死亡的高风险（26%）。相反，LOF 变体与较轻的疾病表现相关。具有这些变异型的个体通常表现为发热诱发的癫痫发作（92%）、程度较轻的运动障碍/智能障碍（85%），并能保持活动功能（85%）。值得注意的是，功能缺失变体个体中没有出现严重运动障碍或小头畸形的报道：数据显示，GABRB2 基因变异可导致功能增益和功能缺失，这种差异与不同的疾病表现相关。利用这些信息，我们构建了一个诊断流程图，通过考虑临床表型，帮助预测最近发现的变体的致病性：本研究由澳大利亚国家健康与医学研究委员会、诺和诺德基金会和灵北基金会资助。

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Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants.

Background: Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABA_A) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants.

Methods: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function.

Findings: Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants.

Interpretation: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes.

Funding: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

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来源期刊

EBioMedicine Biochemistry, 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.