title: Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.
abstract: Cavernous angiomas are vascular malformations mostly located in the central nervous system and characterized by enlarged capillary cavities without intervening brain parenchyma. Clinical symptoms include seizures, haemorrhage and focal neurological deficits. Cavernous angiomas prevalence is close to 0.5% in the general population. They may be inherited as an autosomal dominant condition in as much as 50% of cases. Cerebral cavernous malformations (CCM) loci were previously identified on 7q, 7p and 3q (refs 4,5). A strong founder effect was observed in the Hispano-American population, all families being linked to CCM1 on 7q (refs 4,7). CCM1 locus assignment was refined to a 4-cM interval bracketed by D7S2410 and D7S689 (ref. 8). Here we report a physical and transcriptional map of this interval and that CCM1, a gene whose protein product, KRIT1, interacts with RAP1A (also known as KREV1; ref. 9), a member of the RAS family of GTPases, is mutated in CCM1 families. Our data suggest the involvement of the RAP1A signal transduction pathway in vasculogenesis or angiogenesis.
authors.affiliation: INSERM U25, Faculté de Médecine Necker, 156 Rue de Vaugirard, 75730 Paris Cedex 15, France.
authors.forename: S
authors.initials: S
authors.lastname: Laberge-le Couteulx
authors.forename: H H
authors.initials: HH
authors.lastname: Jung
authors.forename: P
authors.initials: P
authors.lastname: Labauge
authors.forename: J P
authors.initials: JP
authors.lastname: Houtteville
authors.forename: C
authors.initials: C
authors.lastname: Lescoat
authors.forename: M
authors.initials: M
authors.lastname: Cecillon
authors.forename: E
authors.initials: E
authors.lastname: Marechal
authors.forename: A
authors.initials: A
authors.lastname: Joutel
authors.forename: J F
authors.initials: JF
authors.lastname: Bach
authors.forename: E
authors.initials: E
authors.lastname: Tournier-Lasserve
mesh_terms: D000595:Amino Acid Sequence; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006392:Hemangioma, Cavernous / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009154:Mutation; D010375:Pedigree; D020161:Physical Chromosome Mapping; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins