近日，國際神經(jīng)科學前沿期刊《Frontiers in Aging Neuroscience》雜志在線發(fā)表了廈門大學藥學院轉(zhuǎn)化醫(yī)學研究中心(TMRC)曾驥孟教授課題組與廈門大學附屬第一醫(yī)院神經(jīng)內(nèi)科合作的研究論文，研究論文題為《A Novel CCM2 Gene Mutation Associated with Familial Cerebral Cavernous Malformation》。轉(zhuǎn)化醫(yī)學中心博士生-黃文清與第一醫(yī)院魯叢霞主任醫(yī)師為論文共同第一作者，曾驥孟教授與林青主任醫(yī)師為論文共同通訊作者。

顱內(nèi)多發(fā)海綿狀血管瘤(Cerebral Cavernous Malformation, CCM)是一種主要發(fā)生于中樞神經(jīng)系統(tǒng)的血管病變，以嚴重的血管擴張為主要特征。55%左右的CCM患者最初并無癥狀，后期發(fā)展為典型的臨床表現(xiàn)，包括癲癇、腦出血、病灶神經(jīng)學異常和頭痛，其發(fā)病年齡多從20多歲到40多歲。大約50%的CCM是家族遺傳性的，以常染色體顯性遺傳方式存在，在人群中的發(fā)生率為1/2000~1/10000。近年來，三個突變基因-CCM1(KRIT1)、CCM2、CCM3(PDCD10)的發(fā)現(xiàn)及其功能結(jié)構(gòu)的解析(J. Biol. Chem 2010，J. Cell. Biol 2012，F(xiàn)EBS Lett 2013，J. Cell Sci 2014，J. Biol. Chem 2015)為理解CCM的分子致病機制提供重要的依據(jù)與指導。迄今為止，在CCM病例中發(fā)現(xiàn)了多達200個基因突變位點，然而這些位點僅能解釋70%~80% FCCM病例，尚有20%~30% FCCM病例存在其特有的致病突變位點或其他的致病基因(如CCM4 ?)。曾驥孟教授課題組針對廈大附屬第一醫(yī)院神經(jīng)病學專家-魯叢霞和林青兩位主任醫(yī)師臨床診斷的FCCM病例，采用PCR與測序技術(shù)，在CCM2基因上鑒定出了一個新型的移碼突變位點(c.95delC)，此位點的發(fā)現(xiàn)可能為解釋部分中國FCCM患者出現(xiàn)腦出血損傷(CCM lesions)提供依據(jù)。

原文鏈接：

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.