Combinatorial interaction between CCM pathway genes precipitates hemorrhagic stroke

AV Gore, MG Lampugnani, L Dye… - Disease models & …, 2008 - journals.biologists.com
AV Gore, MG Lampugnani, L Dye, E Dejana, BM Weinstein
Disease models & mechanisms, 2008journals.biologists.com
Intracranial hemorrhage (ICH) is a particularly severe form of stroke whose etiology remains
poorly understood, with a highly variable appearance and onset of the disease (;;). In
humans, mutations in any one of three CCM genes causes an autosomal dominant genetic
ICH disorder characterized by cerebral cavernous malformations (CCM). Recent evidence
highlighting multiple interactions between the three CCM gene products and other proteins
regulating endothelial junctional integrity suggests that minor deficits in these other proteins …
Summary
Intracranial hemorrhage (ICH) is a particularly severe form of stroke whose etiology remains poorly understood, with a highly variable appearance and onset of the disease (; ; ). In humans, mutations in any one of three CCM genes causes an autosomal dominant genetic ICH disorder characterized by cerebral cavernous malformations (CCM). Recent evidence highlighting multiple interactions between the three CCM gene products and other proteins regulating endothelial junctional integrity suggests that minor deficits in these other proteins could potentially predispose to, or help to initiate, CCM, and that combinations of otherwise silent genetic deficits in both the CCM and interacting proteins might explain some of the variability in penetrance and expressivity of human ICH disorders. Here, we test this idea by combined knockdown of CCM pathway genes in zebrafish. Reducing the function of rap1b, which encodes a Ras GTPase effector protein for CCM1/Krit1, disrupts endothelial junctions in vivo and in vitro, showing it is a crucial player in the CCM pathway. Importantly, a minor reduction of Rap1b in combination with similar reductions in the products of other CCM pathway genes results in a high incidence of ICH. These findings support the idea that minor polygenic deficits in the CCM pathway can strongly synergize to initiate ICH.
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