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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Sahoo, T; Johnson, EW; Thomas, JW; Kuehl, PM; Jones, TL; Dokken, CG; Touchman, JW; Gallione, CJ; Lee-Lin, SQ; Kosofsky, B; Kurth, JH; Louis, DN; Mettler, G; Morrison, L; Gil-Nagel, A; Rich, SS; Zabramski, JM; Boguski, MS; Green, ED; Marchuk, DA

Published Date

  • November 1999

Published In

Volume / Issue

  • 8 / 12

Start / End Page

  • 2325 - 2333

PubMed ID

  • 10545614

International Standard Serial Number (ISSN)

  • 0964-6906

Digital Object Identifier (DOI)

  • 10.1093/hmg/8.12.2325


  • eng

Conference Location

  • England