Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations
Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations
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DOI：
10.1038/gim.2014.97
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发表时间：
2015-03-01
影响因子：
8.8
通讯作者：
Awad, Issam A.
中科院分区：
文献类型：
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作者：
Shenkar, Robert;Shi, Changbin;Awad, Issam A.
目的：罕见的PDCD10突变引起的脑海绵状血管病的表型表现尚未得到系统的研究，其与Rho激酶介导的高通透性（一种潜在的治疗靶点）的机制联系尚未建立。方法：分析PDCD10小干扰rna处理的内皮细胞的应力纤维、Rho激酶活性和-通透性。评估脑海绵状血管瘤中Rho激酶活性。量化PDCD10突变的前瞻性入选受试者的脑通透性和脑海绵状畸形病变负担，并评估临床表现。结果：我们确定PDCD10蛋白在体外抑制内皮应激纤维、Rho激酶活性和通透性。与其他Ccm基因型相比，Pdcd10杂合小鼠的病变负担更大。我们证明了Rho激酶在小鼠和人类大脑海绵状血管瘤中具有强大的活性，并且PDCD10突变的人的脑血管通透性增加。与更常见的KRIT1和CCM2家族性和散发性脑海绵状畸形相比，临床表型异常侵袭性，病变负担更大，早期出血更频繁。我们首先报道其他表型特征，包括脊柱侧凸、认知障碍和皮肤病变，与病变负荷或出血无关。结论：这些发现定义了一种独特的具有异常侵袭性的脑海绵状血管病，它们为临床前治疗试验、临床咨询和试验设计提供了信息。
Purpose: The phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.Methods: We analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and - permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.Results: We determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.Conclusion: These findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.