Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice
Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice
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DOI：
10.1172/jci44393
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发表时间：
2011-05-01
影响因子：
15.9
通讯作者：
Li, Dean Y.
中科院分区：
文献类型：
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作者：
Chan, Aubrey C.;Drakos, Stavros G.;Li, Dean Y.
脑海绵状血管畸形（CCM）是脑内常见的血管畸形类型，是出血性卒中的主要原因。这种情况已经独立地与3个单独的基因相关：Krevl相互作用捕获（KRIT 1），脑海绵状血管畸形2（CCM 2）和程序性细胞死亡10（PDCD 10）。尽管这3个基因突变引起的疾病病理学具有共性，但我们发现Pdcd 10的缺失导致与Ccm 2和Kritl缺失时所见的发育、细胞生物学和信号传导表型显著不同。PDCD 10结合于生发中心激酶III（GCKIH）家族成员（丝氨酸-苏氨酸激酶的一个子集），并在体内和体外促进内皮细胞的管腔形成。这些发现表明CCM可能是不同机制途径的常见组织表现。然而，Pdcdl 0或Ccm 2的杂合性丢失（洛）导致小鼠中的CCM。通过与基因型特异性人类手术标本直接比较确定，由任一蛋白缺失诱导的小鼠表型再现了在CCM人类患者中观察到的所有关键临床特征。这些结果表明，CCM可以更有效地治疗的基础上指导治疗潜在的基因突变，而不是治疗条件作为一个单一的临床实体。
Cerebral cavernous malformations (CCMs) are a common type of vascular malformation in the brain that are a major cause of hemorrhagic stroke. This condition has been independently linked to 3 separate genes: Krevl interaction trapped (KRIT1), Cerebral cavernous malformation 2 (CCM2), and Programmed cell death 10 (PDCD10). Despite the commonality in disease pathology caused by mutations in these 3 genes, we found that the loss of Pdcd10 results in significantly different developmental, cell biological, and signaling phenotypes from those seen in the absence of Ccm2 and Kritl. PDCD10 bound to germinal center kinase III (GCKIH) family members, a subset of serine-threonine kinases, and facilitated lumen formation by endothelial cells both in vivo and in vitro. These findings suggest that CCM may be a common tissue manifestation of distinct mechanistic pathways. Nevertheless, loss of heterozygosity (LOH) for either Pdcdl 0 or Ccm2 resulted in CCMs in mice. The murine phenotype induced by loss of either protein reproduced all of the key clinical features observed in human patients with CCM, as determined by direct comparison with genotype-specific human surgical specimens. These results suggest that CCM may be more effectively treated by directing therapies based on the underlying genetic mutation rather than treating the condition as a single clinical entity.