Cerebral cavernous malformations: mutations in Krit1.
OBJECTIVE
To find mutations in the recently identified additional exons of the Krit1 gene that causes CCM1, a disease characterized by the formation of cerebral cavernous malformations (CCM). To determine the relative frequency with which Krit1 mutations cause CCM as well as recharacterize the mutations reported in the literature.


METHODS
Twenty-seven families and 11 apparently sporadic individuals affected with CCM were screened for mutations in the Krit1 gene. The gene was screened by single stranded conformation polymorphism, and variants were sequenced. Familial segregation of the mutations was determined.


RESULTS
In familial samples, two new mutations in the novel upstream exons and six additional mutations in the previously identified exons were identified. No mutation was found in any of the sporadic individuals.


CONCLUSIONS
Results demonstrate that the frequency of mutations found in Krit1 is 47% in the families studied and the frequency may increase as more mutations are detected. Mutations are evenly distributed in the gene and do not seem to be limited to structural domains present in Krit1. This is in accordance with the model that Krit1 could be a tumor suppressor gene.
Verlaan
D J
DJ
Center for Research in Neurosciences, Montreal General Hospital, McGill University, Montreal, Quebec, Canada.
Davenport
W J
WJ
Stefan
H
H
Sure
U
U
Siegel
A M
AM
Rouleau
G A
GA
D017089:Ankyrin Repeat / Q000235:genetics; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins