Nature Genetics
23, 189 - 193 (1999)
doi:10.1038/13815
Truncating mutations in CCM1, encoding KRIT1, cause hereditary
cavernous angiomasSophie Laberge-le Couteulx1, Hans H. Jung1, Pierre Labauge1, Jean-Pierre Houtteville2, Christelle Lescoat1, Michaelle Cecillon, Emmanuelle Marechal1, Anne Joutel1, 3, Jean-François Bach1
& Elisabeth Tournier-Lasserve1, 31
INSERM U25, Faculté de Médecine Necker,
156 Rue de Vaugirard, 75730 Paris
Cedex 15, France. 2
Service de Neurochirurgie, CHR Côte de Nacre,
Caen, France. 3
Laboratoire de Cytogénétique, Hôpital
Lariboisière, 2 rue A. Paré, 75010
, Paris, France.
Correspondence should be addressed to Elisabeth Tournier-Lasserve tournier@necker.frCavernous angiomas are vascular malformations mostly located in the central
nervous system and characterized by enlarged capillary cavities without intervening
brain parenchyma1. Clinical symptoms include seizures, haemorrhage
and focal neurological deficits. Cavernous angiomas prevalence is close to
0.5% in the general population2. They may be inherited as an
autosomal dominant condition in as much as 50% of cases3. 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 angiogenesis10.
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