Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice

Abstract

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: Krev1 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 Krit1. PDCD10 bound to germinal center kinase III (GCKIII) 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 Pdcd10 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.

Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice

“…The cerebral blood vessel dilation observed in NgBR mutant embryos bears resemblance to defects observed in CCM gene mutant mice (Boulday et al, 2009; Boulday et al, 2011; Chan et al, 2011; He et al, 2010; Kleaveland et al, 2009; Whitehead et al, 2009; Whitehead et al, 2004). Given that CCM1/2/3 proteins have been identified as responsible for cerebral cavernous malformations (CCMs) (He et al, 2010; Kar et al, 2015), a brain blood vessel assembly defect, we investigated whether these proteins were attenuated in NgBR deficient endothelial cells.…”

Strategy for Identifying Repurposed Drugs for the Treatment of Cerebral Cavernous Malformation

“…Thus, we created mice that are compound heterozygous for a loss of function allele in Ccm2 with the cognate allele flanked by loxp sites permitting its post-natal, endothelial-specific, deletion (PDGFb-iCreER T2 ) 42 . Strikingly, these mice develop CCM lesions that reproduce all of the pathologic aspects of human CCM disease 43 . To our disappointment, four months of simvastatin treatment in this model did not result in a decreased burden of disease, as measured by small animal MRI (Supplementary Fig.…”

The Cerebral Cavernous Malformation Pathway Controls Cardiac Development via Regulation of Endocardial MEKK3 Signaling and KLF Expression

“…Loss of CCM signaling in the postnatal endothelium results in large vascular malformations (CCMs) in the central nervous of humans and mice (Akers et al, 2009; Boulday et al, 2011; Chan et al, 2011; McDonald et al, 2011). CCMs are an important cause of stroke for which there is presently no medical treatment (Li and Whitehead, 2010).…”

“…These studies have identified loss of function mutations in three genes, KRIT1, CCM2 and PDCD10 (reviewed in Riant et al, 2010) that encode intracellular adaptor proteins that associate to form a biochemical complex with the transmembrane protein Heart of Glass (HEG1) (Kleaveland et al, 2009; Zheng et al, 2010). Conditional deletion studies in mice have demonstrated that KRIT1 and CCM2 are required in endothelial cells for branchial arch artery formation at E8.5-9 (Whitehead et al, 2009; Whitehead et al, 2004; Zheng et al, 2010), and to prevent CCM formation in the central nervous system of postnatal animals (Boulday et al, 2011; Chan et al, 2011; McDonald et al, 2011). How CCM signaling regulates endothelial and vascular function remains unclear.…”