Mutations in the Gene Encoding KRIT1, a Krev-1/rap1a Binding Protein, Cause Cerebral Cavernous Malformations (CCM1)

Abstract

Cerebral cavernous malformations (CCM) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. One locus for autosomal dominant CCM ( CCM1 ) maps to chromosome 7q21-q22. Recombination events in linked family members define a critical region of approximately 2 Mb and a shared disease haplotype associated with a presumed founder effect in families of Mexican-American descent points to a potentially smaller region of interest. Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene. Seven different KRIT1 mutations have been identified in 23 distinct CCM1 families. The identical mutation is present in 16 of 21 Mexican-American families analyzed, substantiating a founder effect in this population. Other Mexican-American and non-Hispanic Caucasian CCM1 kindreds harbor other KRIT1 mutations. Identification of a common Mexican-American mutation has potential clinical significance for presymptomatic diagnosis of CCM in this population. In addition, these data point to a key role for the Krev-1/rap1a signaling pathway in angiogenesis and cerebrovascular disease.

Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus

“…Coding exons of the Krit1 and MGC4607 genes were amplified using primers described previously (Sahoo, et al, 1999;Liquori, et al, 2003). Coding exons of the PDCD10 gene were amplified using the following primers:…”

“…Based on the linkage of 20 families, Craig et al (Craig, et al, 1998) reported that CCM1 would account for 40% of all familial CCM cases, CCM2 would account for 20%, and CCM3 would account for 40%. The disease gene responsible for CCM1 encodes KRIT1 (KREV Interaction Trapped 1) (Laberge, et al, 1999;Sahoo, et al, 1999), and the disease gene for CCM2 encodes malcavernin (Liquori, et al, 2003;Denier, et al, 2004). Recently, mutations were identified in the PDCD10 (programmed cell death 10) gene in families not exhibiting KRIT1 or malcavernin mutations (Bergametti, et al, 2005), thus identifying a third causative gene.…”

Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with Cerebral Cavernous Malformations

“…6,7 Recently, CCM1 was identified as the KRIT1 gene. 8,9 KRIT1, a protein of unknown function so far, was previously identified through a yeast two-hybrid screen designed to identify proteins interacting with Rap1A, a small Ras like GTPase protein. 10 KRIT1 encodes a 736 amino-acids protein containing four ankyrin domains, a FERM domain and a C-terminal portion interacting with Rap1A.…”

CCM1 and the second life of proteins in adhesion complexes

“…33,34 Later on, two other genes were found to be associated with CCM, CCM2/ OSM (osmosensing protein 1)/Malcavernin 35,36 and CCM3/ PDCD10 (programmed cell death 10). 37,38 Over 150 different germline mutations are identified in either one of these genes, predominantly resulting in loss of function.…”

“…Of the three CCM proteins, KRIT1/CCM1, is the first protein identified related to CCM 33,34 and is most extensively studied compared with CCM2 and CCM3. Therefore, we will predominantly focus on the molecular details described for CCM1.…”