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- Title
Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1).
- Authors
Sahoo, T; Johnson, E W; Thomas, J W; Kuehl, P M; Jones, T L; Dokken, C G; Touchman, J W; Gallione, C J; Lee-Lin, S Q; Kosofsky, B; Kurth, J H; Louis, D N; Mettler, G; Morrison, L; Gil-Nagel, A; Rich, S S; Zabramski, J M; Boguski, M S; Green, E D; Marchuk, D A
- 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.
- Publication
Human molecular genetics, 1999, Vol 8, Issue 12, p2325
- ISSN
0964-6906
- Publication type
Journal Article
- DOI
10.1093/hmg/8.12.2325