Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1)

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 domina nt CCM (CCM1) maps to chromosome 7q21-q22. Recombination events in linked f amily members define a critical region of similar to 2 Mb and a shared dise ase haplotype associated with a presumed founder effect in families of Mexi can-American descent points to a potentially smaller region of interest. Us ing a genomic sequence-based positional cloning strategy, we have identifie d KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor supp ressor, as the CCM1 gene. Seven different KRIT1 mutations have been identif ied in 23 distinct CCM1 families. The identical mutation is present in 16 o f 21 Mexican-American families analyzed, substantiating a founder effect in this population. Other Mexican-American and non-Hispanic Caucasian CCM1 ki ndreds harbor other KRIT1 mutations. Identification of a common Mexican-Ame rican mutation has potential clinical significance for presymptomatic diagn osis 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.