Severity of GNAO1-Related Disorder Correlates with Changes in G-Protein Function

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY

Annals of Neurology Pub Date : 2023-08-07 DOI:10.1002/ana.26758

Jana Domínguez-Carral MD, William Grant Ludlam PhD, Mar Junyent Segarra BS, Montserrat Fornaguera Marti BS, Sol Balsells MsC, Jordi Muchart MD, Dunja Čokolić Petrović MD, Iván Espinoza MD, Juan Dario Ortigoza-Escobar MD, PhD, Kirill A. Martemyanov PhD, GNAO1-Study Group

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引用次数: 0

Abstract

Objective

GNAO1-related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are characterized by developmental delay or intellectual disability, hypotonia, movement disorders, and epilepsy. Neither a genotype–phenotype correlation nor a clear severity score have been established for this disorder. The objective of this prospective and retrospective observational study was to develop a severity score for GNAO1-related disorders, and to delineate the correlation between the underlying molecular mechanisms and clinical severity.

Methods

A total of 16 individuals with GNAO1-related disorders harboring 12 distinct missense variants, including four novel variants (p.K46R, p.T48I, p.R209P, and p.L235P), were examined with repeated clinical assessments, video-electroencephalogram monitoring, and brain magnetic resonance imaging. The molecular pathology of each variant was delineated using a molecular deconvoluting platform.

Results

The patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well represented in the GNAO1-related disorders severity score, with a broad range of results. Patients with the same variant had comparable severity scores, indicating that differences in disease profiles are not due to interpatient variability, but rather, to unique disease mechanisms. Moreover, we found a significant correlation between clinical severity scores and molecular mechanisms.

Interpretation

The clinical score proposed here provides further insight into the correlation between pathophysiology and phenotypic severity in GNAO1-related disorders. We found that each variant has a unique profile of clinical phenotypes and pathological molecular mechanisms. These findings will contribute to better understanding GNAO1-related disorders. Additionally, the severity score will facilitate standardization of patients categorization and assessment of response to therapies in development. ANN NEUROL 2023;94:987–1004

Abstract Image

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GNAO1相关疾病的严重程度与G蛋白功能的变化相关。

目的：由GNAO1基因变异引起的GNAO1相关疾病（OMIM#615473和#617493）以发育迟缓或智力残疾、张力减退、运动障碍和癫痫为特征。该疾病的基因型-表型相关性和明确的严重程度评分均未确定。这项前瞻性和回顾性观察性研究的目的是制定GNAO1相关疾病的严重程度评分，并描述潜在分子机制与临床严重程度之间的相关性。方法：共有16名GNAO1相关疾病患者携带12种不同的错义变体，包括四种新变体（p.K46R、p.T48I、p.R209P和p.L235P），通过重复临床评估、视频脑电图监测和脑磁共振成像进行检查。使用分子去卷积平台描绘每个变体的分子病理学。结果：患者的症状严重程度存在很大差异。这种异质性在GNAO1相关疾病严重程度评分中得到了很好的体现，结果范围很广。具有相同变体的患者具有可比的严重程度评分，这表明疾病特征的差异不是由于患者间的变异性，而是由于独特的疾病机制。此外，我们发现临床严重程度评分与分子机制之间存在显著相关性。解释：本文提出的临床评分为GNAO1相关疾病的病理生理学和表型严重程度之间的相关性提供了进一步的见解。我们发现，每种变体都有独特的临床表型和病理分子机制。这些发现将有助于更好地理解GNAO1相关疾病。此外，严重程度评分将有助于患者分类的标准化和对正在开发的治疗反应的评估。神经网络2023；94:987-104。

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.