KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation

Abstract

Hyperkeratotic capillary-venous malformations (HCCVMs) are rare cutaneous lesions that occur in a small subgroup of patients with cerebral capillary malformation (CCM). CCMs cause neurological problems that range from headaches to life-threatening intracranial bleeding. CCMs and HCCVMs have a similar histopathological appearance of dilated capillary-venous channels. Genetic linkage of inherited CCMs has been established to three chromosomal loci, 3q25. 2-27, 7p13-15 and 7q21-22. The first mutations were identified in the CCM1 gene (located on 7q21-22), which encodes KRIT1 protein (KREV1 interaction trapped 1), presumably a membrane-bound protein with signalling activity. Although KRIT1 is known to interact with KREV1/RAP1A, a Ras-family GTPase, the exact function of KRIT1 in the formation of cerebral capillaries and veins is poorly understood. In this study, we screened five families with CCM for mutations in the KRIT1 gene. In one of the families, CCMs co-segregated with HCCVMs. We identified a KRIT1Delta(G103)mutation in this family, suggesting that this rare form of the condition is also caused by mutations in the CCM1 gene and that KRIT1 is probably important for cutaneous vasculature. Interestingly, this deletion introduces the earliest stop codon among identified mutations, suggesting a possible correlation between the molecular alteration and the cutaneous phenotype. Another novel mutation, KRIT1(IVS2+2(T-->C)), was found in a family with only cerebral capillary-venous malformations.

Loss of p53 Sensitizes Mice with a Mutation in Ccm1 (KRIT1) to Development of Cerebral Vascular Malformations

“…No gross lesions were observed on cursory examination of the other internal organs. Because cutaneous vascular lesions have been reported in some human CCM patients, 3 we flayed several Ccm1 ϩ/Ϫ Trp53 Ϫ/Ϫ animals and examined the underside of the skin. No vascular lesions were visible.…”

“…Cavernous malformations can form in any part of the central nervous system, and some patients with CCM also have cutaneous vascular malformations. 3 Hemorrhaging of the vessels in a cavernous malformation can result in headaches, seizures, and stroke, that are sometimes lethal.…”

CCM3 signaling through sterile 20–like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations

“…Familial CCMs are inherited in an autosomal dominant pattern, constitute up to 50% of CCM cases, and have been found to be associated with loss-of-function mutations in 3 genes, KRIT1 (also known as CCM1) (1)(2)(3), CCM2 (MALCAVERNIN, OSM) (4,5), and PDCD10 (CCM3) (6,7). Genetic studies in zebrafish have demonstrated that loss of ccm1, ccm2, or the transmembrane receptor heart of glass (heg) results in embryonic cardiovascular phenotypes characterized by a large, thin-walled heart and defective branchial arch artery development that prevents blood circulation (8)(9)(10).…”

Pathogenesis of hemangioma

“…This dearth of molecular details is striking, considering the growing list of germline mutations in genes causing specific inherited syndromes involving vascular malformations, including hereditary hemorrhagic telangiectasia (4,5), cutaneous venous malformations (6), cerebral cavernous malformations (7,8), and hyperkeratotic cutaneous capillary-venous malformation (9). Are we able to investigate hemangioma in a similar manner?…”