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

Hyperkeratotic capillary-venous malformations (HCCVMs) are rare cutaneous l esions that occur in a small subgroup of patients with cerebral capillary m alformation (CCM). CCMs cause neurological problems that range from headach es to life-threatening intracranial bleeding, CCMs and HCCVMs have a simila r histopathological appearance of dilated capillary-venous channels. Geneti c 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 interac tion trapped 1), presumably a membrane-bound protein with signalling activi ty. Although KRIT1 is known to interact with KREV1/RAP1A, a Ras-family GTPa se, the exact function of KRIT1 in the formation of cerebral capillaries an d 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-segre gated with HCCVMs. We identified a KRIT1 Delta(G103) mutation in this famil y, suggesting that this rare form of the condition is also caused by mutati ons in the CCM1 gene and that KRIT1 is probably important for cutaneous vas culature. Interestingly, this deletion introduces the earliest stop codon a mong identified mutations, suggesting a possible correlation between the mo lecular alteration and the cutaneous phenotype. Another novel mutation, KRI T1(IVS2+2(T-->C)), was found in a family with only cerebral capillary-venou s malformations.