近日，国际神经科学前沿期刊《Frontiers in Aging Neuroscience》杂志在线发表了厦门大学药学院转化医学研究中心(TMRC)曾骥孟教授课题组与厦门大学附属第一医院神经内科合作的研究论文，研究论文题为《A Novel CCM2 Gene Mutation Associated with Familial Cerebral Cavernous Malformation》。转化医学中心博士生-黄文清与第一医院鲁丛霞主任医师为论文共同第一作者，曾骥孟教授与林青主任医师为论文共同通讯作者。
颅内多发海绵状血管瘤(Cerebral Cavernous Malformation, CCM)是一种主要发生于中枢神经系统的血管病变，以严重的血管扩张为主要特征。55%左右的CCM患者最初并无症状，后期发展为典型的临床表现，包括癫痫、脑出血、病灶神经学异常和头痛，其发病年龄多从20多岁到40多岁。大约50%的CCM是家族遗传性的，以常染色体显性遗传方式存在，在人群中的发生率为1/2000~1/10000。近年来，三个突变基因-CCM1(KRIT1)、CCM2、CCM3(PDCD10)的发现及其功能结构的解析(J. Biol. Chem 2010，J. Cell. Biol 2012，FEBS Lett 2013，J. Cell Sci 2014，J. Biol. Chem 2015)为理解CCM的分子致病机制提供重要的依据与指导。迄今为止，在CCM病例中发现了多达200个基因突变位点，然而这些位点仅能解释70%~80% FCCM病例，尚有20%~30% FCCM病例存在其特有的致病突变位点或其他的致病基因(如CCM4 ?)。曾骥孟教授课题组针对厦大附属第一医院神经病学专家-鲁丛霞和林青两位主任医师临床诊断的FCCM病例，采用PCR与测序技术，在CCM2基因上鉴定出了一个新型的移码突变位点(c.95delC)，此位点的发现可能为解释部分中国FCCM患者出现脑出血损伤(CCM lesions)提供依据。
原文链接：
A Novel CCM2 GENE Mutation Associated with Familial Cerebral Cavernous Malformation
原文摘要：
Background: Cerebral cavernous malformations (CCMs) are common vascular malformations that predominantly arise in the central nervous system and are mainly characterized by enlarged vascular cavities without intervening brain parenchyma. Familial CCMs (FCCMs) is inherited in an autosomal dominant pattern with incomplete penetrance and variable symptoms.
Methods: Mutations of three pathogenic genes, CCM1, CCM2, and CCM3, were investigated by direct DNA sequencing in a Chinese family with multiple CCM lesions.
Results: Four heterozygous variants in the CCM2 gene, including one deletion (c.95delC), a missense mutation (c.358G>A, p.V120I), one silent mutation (c.915G>A, p.T305T), and a substitution (c. *1452 T>C), were identified in the subjects with multiple CCM lesions, but not in a healthy sibling. Among these variants, the c.95delC deletion is a novel mutation which is expected to cause a premature termination codon. It is predicted to produce a truncated CCM2 protein lacking the PTB and C-terminal domains, thus disrupting the molecularfunctions of CCM2.
Conclusions: The novel truncating mutation in the CCM2 gene, c.95delC, may be responsible for multiple CCM lesions in a part of FCCM. In addition, it may represent a potential genetic biomarker for early diagnosis of FCCM.
