Useful insights into innovative approaches for CCM disease prevention and treatment are emerging from a growing understanding of the biological functions of the three known CCM proteins, CCM1/KRIT1, CCM2 and CCM3/PDCD10.
Our finding suggests that the novel nonsense mutation c.1159G>T in CCM1 gene is associated with FCCM, and that CCM1 haploinsufficiency may be the underlying mechanism of CCMs.
Endothelial cell-specific ablation of Ccm1 and Ccm2 in different mouse models led to the formation of CCM-like lesions, which were poorly covered by periendothelial cells.
Familial cerebral cavernous malformations (CCMs) are predominantly neurovascular lesions and are associated with mutations within the KRIT1, CCM2, and PDCD10 genes.
Familial CCM1 carriers have not only an increased number of cerebral cavernous malformations but also an increased number of white matter T2 hyperintensities, spatially distinct from cerebral cavernous malformations, which exceeded that of a healthy population.
KRIT1 loss-of-function activates the mTOR-ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole-cular and cellular phenotypes associated with CCM.
Cerebral cavernous malformations (CCM) are vascular dysplasias that usually occur in the brain and are associated with mutations in the KRIT1/CCM1, CCM2/MGC4607/OSM/Malcavernin, and PDCD10/CCM3/TFAR15 genes.
Familial CCM type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and is characterized by multiple brain lesions whose number and size increase with age.
Cerebral cavernous malformation (CCM) is a disease of vascular malformations known to be caused by mutations in one of three genes: CCM1, CCM2 or CCM3.
Mutations in KRIT1, CCM2, and PDCD10 also underlie human cerebral cavernous malformation (CCM) and postnatal loss of these genes in the mouse endothelium results in rapid CCM formation.
The mutation detection rate for familial cerebral cavernous malformations (CCM) is extremely high, being about 90 % if direct sequencing of the three genes, CCM1, CCM2, and CCM3, is used in conjunction with quantitative analyses to detect larger CCM1-3 deletions/duplications.
Taken together with the reported role of c-Jun in vascular dysfunctions triggered by oxidative stress, our findings shed new light on the molecular mechanisms underlying KRIT1 function and CCM pathogenesis.
Thus, increased TGF-β and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease.
Cerebral cavernous malformations (CCMs) are vascular lesions that can occur sporadically or as a consequence of inherited loss-of-function mutations, predominantly in the genes CCM1 (KRIT1), CCM2 (MGC4607, OSM, Malcavernin), or CCM3 (PDCD10, TFAR15).