Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC 27710, USA.
Hum Mol Genet. 2011 Jan 15;20(2):211-22. doi: 10.1093/hmg/ddq433. Epub 2010 Oct 11.
Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system appearing as multicavernous, blood-filled capillaries, leading to headache, seizure and hemorrhagic stroke. CCM occurs either sporadically or as an autosomal dominant disorder caused by germline mutation of one of the three genes: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. Surgically resected human CCM lesions have provided molecular and immunohistochemical evidence for a two-hit (germline plus somatic) mutation mechanism. In contrast to the equivalent human genotype, mice heterozygous for a Ccm1- or Ccm2-null allele do not develop CCM lesions. Based on the two-hit hypothesis, we attempted to improve the penetrance of the model by crossing Ccm1 and Ccm2 heterozygotes into a mismatch repair-deficient Msh2(-/-) background. Ccm1(+/-)Msh2(-/-) mice exhibit CCM lesions with high penetrance as shown by magnetic resonance imaging and histology. Significantly, the CCM lesions range in size from early-stage, isolated caverns to large, multicavernous lesions. A subset of endothelial cells within the CCM lesions revealed somatic loss of CCM protein staining, supporting the two-hit mutation mechanism. The late-stage CCM lesions displayed many of the characteristics of human CCM lesions, including hemosiderin deposits, immune cell infiltration, increased endothelial cell proliferation and increased Rho-kinase activity. Some of these characteristics were also seen, but to a lesser extent, in early-stage lesions. Tight junctions were maintained between CCM lesion endothelial cells, but gaps were evident between endothelial cells and basement membrane was defective. In contrast, the Ccm2(+/-)Msh2(-/-) mice lacked cerebrovascular lesions. The CCM1 mouse model provides an in vivo tool to investigate CCM pathogenesis and new therapies.
脑静脉畸形（CCM）是中枢神经系统的血管病变，表现为多腔、充满血液的毛细血管，导致头痛、癫痫发作和出血性中风。CCM 要么是散发性的，要么是常染色体显性遗传病，由三个基因中的一个种系突变引起：CCM1/KRIT1、CCM2/MGC4607 和 CCM3/PDCD10。手术切除的人类 CCM 病变提供了分子和免疫组织化学证据，证明存在两次打击（种系加体细胞）突变机制。与等效的人类基因型相比，杂合 Ccm1 或 Ccm2 缺失等位基因的小鼠不会发生 CCM 病变。基于两次打击假说，我们试图通过将 Ccm1 和 Ccm2 杂合子杂交到错配修复缺陷的 Msh2(-/-)背景中来提高模型的外显率。Ccm1(+/-)Msh2(-/-) 小鼠表现出高外显率的 CCM 病变，如磁共振成像和组织学所示。重要的是，CCM 病变的大小范围从早期孤立的腔到大型多腔病变。CCM 病变内的一部分内皮细胞显示出 CCM 蛋白染色的体细胞缺失，支持两次打击突变机制。晚期 CCM 病变表现出许多人类 CCM 病变的特征，包括含铁血黄素沉积、免疫细胞浸润、内皮细胞增殖增加和 Rho-激酶活性增加。这些特征中的一些也在早期病变中看到，但程度较轻。CCM 病变内皮细胞之间保持紧密连接，但内皮细胞之间存在间隙，基底膜存在缺陷。相比之下，Ccm2(+/-)Msh2(-/-) 小鼠缺乏脑血管病变。CCM1 小鼠模型为研究 CCM 发病机制和新疗法提供了一种体内工具。
