McDonald David A, Shi Changbin, Shenkar Robert, Gallione Carol J, Akers Amy L, Li Stephanie, De Castro Nicholas, Berg Michel J, Corcoran David L, Awad Issam A, Marchuk Douglas A
Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC 27710, USA.
Section of Neurosurgery, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
Hum Mol Genet. 2014 Aug 15;23(16):4357-70. doi: 10.1093/hmg/ddu153. Epub 2014 Apr 3.
Cerebral cavernous malformations (CCMs) are vascular lesions affecting the central nervous system. CCM occurs either sporadically or in an inherited, autosomal dominant manner. Constitutional (germline) mutations in any of three genes, KRIT1, CCM2 and PDCD10, can cause the inherited form. Analysis of CCM lesions from inherited cases revealed biallelic somatic mutations, indicating that CCM follows a Knudsonian two-hit mutation mechanism. It is still unknown, however, if the sporadic cases of CCM also follow this genetic mechanism. We extracted DNA from 11 surgically excised lesions from sporadic CCM patients, and sequenced the three CCM genes in each specimen using a next-generation sequencing approach. Four sporadic CCM lesion samples (36%) were found to contain novel somatic mutations. Three of the lesions contained a single somatic mutation, and one lesion contained two biallelic somatic mutations. Herein, we also describe evidence of somatic mosaicism in a patient presenting with over 130 CCM lesions localized to one hemisphere of the brain. Finally, in a lesion regrowth sample, we found that the regrown CCM lesion contained the same somatic mutation as the original lesion. Together, these data bolster the idea that all forms of CCM have a genetic underpinning of the two-hit mutation mechanism in the known CCM genes. Recent studies have found aberrant Rho kinase activation in inherited CCM pathogenesis, and we present evidence that this pathway is activated in sporadic CCM patients. These results suggest that all CCM patients, including those with the more common sporadic form, are potentially amenable to the same therapy.
脑海绵状血管畸形（CCMs）是影响中枢神经系统的血管病变。CCM可散发出现，也可呈常染色体显性遗传方式遗传。KRIT1、CCM2和PDCD10这三个基因中任何一个发生的胚系（种系）突变都可导致遗传形式。对遗传性病例的CCM病变分析显示存在双等位基因体细胞突变，这表明CCM遵循Knudsonian两次打击突变机制。然而，散发性CCM病例是否也遵循这种遗传机制仍不清楚。我们从散发性CCM患者手术切除的11个病变中提取了DNA，并使用下一代测序方法对每个样本中的三个CCM基因进行了测序。发现四个散发性CCM病变样本（36%）含有新的体细胞突变。其中三个病变含有单个体细胞突变，一个病变含有两个双等位基因体细胞突变。在此，我们还描述了一名患者的体细胞镶嵌现象的证据，该患者大脑一侧半球有超过130个CCM病变。最后，在一个病变再生样本中，我们发现再生的CCM病变与原始病变含有相同的体细胞突变。总之，这些数据支持了所有形式的CCM在已知CCM基因中都有两次打击突变机制的遗传基础这一观点。最近的研究发现遗传性CCM发病机制中存在异常的Rho激酶激活，我们提供的证据表明该途径在散发性CCM患者中也被激活。这些结果表明，所有CCM患者，包括那些更常见的散发性形式的患者，都可能适合相同的治疗方法。
