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Cerebral cavernous malformations

Mutations in Krit1

From the Center for Research in Neurosciences (D.J. Verlaan, and Drs. Davenport and Rouleau), Montreal General Hospital, and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; Kopfklinikum (Dr. Stefan), University of Erlangen Nurnberg, and Department of Neurosurgery (Dr. Sure), University of Marburg, Germany; and Epilepsy Program (Dr. Siegal), Department of Neurology, University Hospital Zürich, Switzerland.

Address correspondence and reprint requests to Dr. Guy Rouleau, Center for Research in Neurosciences, 1650 Cedar Ave., Montreal, Quebec H3G 1A4, Canada; e-mail: mi32{at}musica.mcgill.ca

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.

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