A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells

被引：146

作者：

Pagenstecher, Axel ^{[2
]}

Stahl, Sonja

Sure, Ulrich ^{[3
]}

Felbor, Ute ^{[1
]}

机构：

[1] Univ Wurzburg, Dept Human Genet, Bioctr, D-97074 Wurzburg, Germany

[2] Univ Marburg, Dept Neuropathol, D-35032 Marburg, Germany

[3] Univ Essen Gesamthsch, Dept Neurosurg, Essen, Germany

来源：

HUMAN MOLECULAR GENETICS | 2009年 / 18卷 / 05期

关键词：

VASCULAR MALFORMATIONS; KRIT1; GENE; MUTATION; EXPRESSION; DELETIONS;

D O I：

10.1093/hmg/ddn420

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cavernous vascular malformations occur with a frequency of 1:200 and can cause recurrent headaches, seizures and hemorrhagic stroke if located in the brain. Familial cerebral cavernous malformations (CCMs) have been associated with germline mutations in CCM1/KRIT1, CCM2 or CCM3/PDCD10. For each of the three CCM genes, we here show complete localized loss of either CCM1, CCM2 or CCM3 protein expression depending on the inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein but not for the two others. In addition to proving loss of function at the protein level, our data are the first to demonstrate endothelial cell mosaicism within cavernous tissues and provide clear pathogenetic evidence that the endothelial cell is the cell of disease origin.

引用

页码：911 / 918

页数：8

共 33 条

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