Severity of GNAO1-Related Disorder Correlates with Changes in G-Protein Function.
Severity of GNAO1-Related Disorder Correlates with Changes in G-Protein Function.
复制标题
GNAO1 相关疾病的严重程度与 G 蛋白功能的变化相关。
DOI：
10.1002/ana.26758
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发表时间：
2023
影响因子：
11.2
通讯作者：
GNAO1-StudyGroup
中科院分区：
文献类型：
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作者：
Domínguez-Carral,Jana;Ludlam,WilliamGrant;JunyentSegarra,Mar;FornagueraMarti,Montserrat;Balsells,Sol;Muchart,Jordi;ČokolićPetrović,Dunja;Espinoza,Iván;Ortigoza-Escobar,JuanDario;Martemyanov,KirillA;GNAO1-StudyGroup
GNAO 1相关疾病（OMIM #615473和#617493）由GNAO 1基因变异引起，其特征为发育迟缓或智力残疾、张力减退、运动障碍和癫痫。对于这种疾病，既没有基因型-表型相关性，也没有明确的严重程度评分。这项前瞻性和回顾性观察性研究的目的是为GNAO 1相关疾病制定一个严重程度评分，并描述潜在的分子机制和临床严重程度之间的相关性。（p.K46R、p.T48I、p.R209P和p.L235P）进行了重复临床评估、视频脑电图监测和脑磁共振成像检查。使用分子去卷积platform.ResultsThe患者表现出广泛的变异，他们的症状的严重程度的分子病理学划定。这种异质性在GNAO 1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。具有相同变异的患者具有可比的严重程度评分，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和分子机制之间存在显著相关性。解释这里提出的临床评分提供了对GNAO 1相关疾病中病理生理学和表型严重程度之间相关性的进一步了解。我们发现，每种变异都具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GNAO 1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开发中治疗的反应评估。神经网络2023;94：987-1004
ObjectiveGNAO1‐related disorders (OMIM #615473 and #617493), caused by variants in theGNAO1gene, 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 forGNAO1‐related disorders, and to delineate the correlation between the underlying molecular mechanisms and clinical severity.MethodsA total of 16 individuals withGNAO1‐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.ResultsThe patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well represented in theGNAO1‐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.InterpretationThe clinical score proposed here provides further insight into the correlation between pathophysiology and phenotypic severity inGNAO1‐related disorders. We found that each variant has a unique profile of clinical phenotypes and pathological molecular mechanisms. These findings will contribute to better understandingGNAO1‐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