Universidade Federal do Estado do Rio de Janeiro, Laboratório de Neurociências Translacional, Programa de Pós-Graduação em Neurologia, Rio de Janeiro RJ, Brasil; Universidade Federal do Rio de Janeiro, Hospital Universitário Clementino Fraga Filho, Departamento de Neurocirurgia, Rio de Janeiro RJ, Brasil.
Universidade Estadual do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Departamento de Farmacologia e Psicobiologia, Rio de Janeiro RJ, Brasil; Universidade Federal do Estado do Rio de Janeiro, Instituto Biomédico, Rio de Janeiro RJ, Brasil.
J Stroke Cerebrovasc Dis. 2024 Nov;33(11):107947. doi: 10.1016/j.jstrokecerebrovasdis.2024.107947. Epub 2024 Aug 23.
Cerebral Cavernous Malformations (CCM) is a genetic disease characterized by vascular abnormalities in the brain and spinal cord, affecting 0.4-0.5 % of the population. We identified two novel pathogenic mutations, CCM1/KRIT1 c.811delT (p.Trp271GlyfsTer5) and CCM2/MGC4607 c.613_614insGG p.Glu205GlyfsTer31), which disrupt crucial protein domains and potentially alter disease progression.
The study aims to comprehensively analyze a Brazilian cohort of CCM patients, integrating genetic, clinical, and structural aspects. Specifically, we sought to identify novel mutations within the CCM complex, and explore their potential impact on disease progression.
We conducted a detailed examination of neuroradiological and clinical features in both symptomatic and asymptomatic CCM patients, performing genetic analyses through sequencing of the CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes In silico structural predictions were carried out using PolyPhen-2, SIFT, and Human Genomics Community tools. Protein-protein interactions and docking analyses were explored using the STRING database.
Genetic analysis identifies 6 pathogenic mutations, 4 likely pathogenic, 1 variants of uncertain significance, and 7 unclassified mutations, including the novel mutations in CCM1 c.811delT and CCM2 c.613_614insGG. In silico structural analysis revealed significant alterations in protein structure, supporting their pathogenicity. Protein-protein interaction analysis indicated nuanced impacts on cellular processes. Clinically, we observed a broad spectrum of symptoms, including seizures and focal neurological deficits. However, no statistically significant differences were found in lesion burden, age of first symptom onset, or sex between the identified CCM1/KRIT1 and CCM2/MGC4607 mutations among all patients studied.
This study enhances the understanding of CCM by linking clinical variability, genetic mutations, and structural effects. The identification of these novel mutations opens new avenues for research and potential therapeutic strategies.
脑动静脉畸形（CAVM）是一种以脑脊髓血管异常为特征的遗传性疾病，影响人群的 0.4-0.5%。我们鉴定了两个新的致病突变，CCM1/KRIT1 c.811delT（p.Trp271GlyfsTer5）和 CCM2/MGC4607 c.613_614insGG p.Glu205GlyfsTer31），它们破坏了关键的蛋白质结构域，可能改变了疾病的进展。
本研究旨在综合分析巴西 CAVM 患者队列，整合遗传、临床和结构方面。具体来说，我们试图在 CCM 复合物中发现新的突变，并探索它们对疾病进展的潜在影响。
我们对有症状和无症状的 CAVM 患者进行了详细的神经影像学和临床特征检查，通过对 CCM1/KRIT1、CCM2/MGC4607 和 CCM3/PDCD10 基因进行测序进行基因分析。使用 PolyPhen-2、SIFT 和人类基因组社区工具进行了结构预测。使用 STRING 数据库进行了蛋白质-蛋白质相互作用和对接分析。
遗传分析鉴定出 6 个致病突变、4 个可能致病突变、1 个意义不确定的变异和 7 个未分类的突变，包括 CCM1 c.811delT 和 CCM2 c.613_614insGG 的新突变。结构分析显示蛋白质结构发生了显著改变，支持其致病性。蛋白质-蛋白质相互作用分析表明对细胞过程有细微的影响。临床上，我们观察到广泛的症状，包括癫痫发作和局灶性神经功能缺损。然而，在所研究的所有患者中，未发现鉴定的 CCM1/KRIT1 和 CCM2/MGC4607 突变之间在病变负担、首次症状发作年龄或性别方面有统计学差异。
本研究通过将临床变异性、遗传突变和结构效应联系起来，加深了对 CCM 的理解。这些新突变的鉴定为研究和潜在的治疗策略开辟了新的途径。
