title: 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.
authors.affiliation: Department of Genetics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: T
authors.initials: T
authors.lastname: Sahoo
authors.forename: E W
authors.initials: EW
authors.lastname: Johnson
authors.forename: J W
authors.initials: JW
authors.lastname: Thomas
authors.forename: P M
authors.initials: PM
authors.lastname: Kuehl
authors.forename: T L
authors.initials: TL
authors.lastname: Jones
authors.forename: C G
authors.initials: CG
authors.lastname: Dokken
authors.forename: J W
authors.initials: JW
authors.lastname: Touchman
authors.forename: C J
authors.initials: CJ
authors.lastname: Gallione
authors.forename: S Q
authors.initials: SQ
authors.lastname: Lee-Lin
authors.forename: B
authors.initials: B
authors.lastname: Kosofsky
authors.forename: J H
authors.initials: JH
authors.lastname: Kurth
authors.forename: D N
authors.initials: DN
authors.lastname: Louis
authors.forename: G
authors.initials: G
authors.lastname: Mettler
authors.forename: L
authors.initials: L
authors.lastname: Morrison
authors.forename: A
authors.initials: A
authors.lastname: Gil-Nagel
authors.forename: S S
authors.initials: SS
authors.lastname: Rich
authors.forename: J M
authors.initials: JM
authors.lastname: Zabramski
authors.forename: M S
authors.initials: MS
authors.lastname: Boguski
authors.forename: E D
authors.initials: ED
authors.lastname: Green
authors.forename: D A
authors.initials: DA
authors.lastname: Marchuk
mesh_terms: D001808:Blood Vessels / Q000002:abnormalities*; D001921:Brain / Q000098:blood supply*; D005006:Ethnicity; D008040:Genetic Linkage; D006801:Humans; D000075927:KRIT1 Protein; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D020161:Physical Chromosome Mapping; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins