This Article Full Text Full Text (PDF) All Versions of this Article: 36/4/872    most recent 01.STR.0000157586.20479.fdv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gault, J. Articles by Awad, I. A. Search for Related Content PubMed PubMed Citation Articles by Gault, J. Articles by Awad, I. A. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Genetics Home Reference Related Collections Cerebrovascular disease/stroke Genetics of Stroke Other Vascular biology

(Stroke. 2005;36:872.)
© 2005 American Heart Association, Inc.

Research Reports

Biallelic Somatic and Germ Line CCM1 Truncating Mutations in a Cerebral Cavernous Malformation Lesion

From the Department of Neurosurgery (J.G., P.R.), University of Colorado Health Sciences Center, Denver, Colo; and the Department of Neurosurgery (R.S., I.A.A.), Evanston Northwestern Healthcare, Evanston, Ill.

Correspondence to Judith Gault, 4200 E. 9th Ave, C307, Denver, CO 80262. E-mail judith.gault{at}uchsc.edu

Background and Purpose— Cerebral cavernous malformations (CCMs) are focal dysmorphic blood vessel anomalies that predispose patients to hemorrhagic stroke and epilepsy. CCMs are sporadic or inherited and 3 genes (CCM1, CCM2, and CCM3) have been identified. However, the role of somatic mutation in CCM genesis has been disputed. The hypothesis that somatic mutations contribute to CCM lesion genesis is tested.

Methods— Mutations were identified by analysis of polymerase chain reaction (PCR) products spanning the 16 CCM1 coding exons with denaturing high-pressure liquid chromatography (DHPLC), cloning, and sequencing. Somatic mutation was verified 3 ways in lesion DNA and RNA samples. The somatic and germ line mutations were shown to be biallelic using allele specific reverse-transcribed PCR amplification and sequence analyses.

Results— A somatic 34-nucleotide deletion in CCM1 is identified in a CCM lesion along with a germ line CCM1 mutation (Q455X). The somatic mutation is not present in DNA or RNA isolated from the patient’s blood. These 2 genetic hits are biallelic.

Conclusions— Identification of biallelic CCM1 somatic and germ line truncating mutations strongly support the "two-hit" mechanism in this CCM lesion.

Key Words: genetics • mutation • stroke, hemorrhagic • vascular malformations

This article has been cited by other articles:

				P. Brouillard and M. Vikkula Genetic causes of vascular malformations Hum. Mol. Genet., October 15, 2007; 16(R2): R140 - R149. [Abstract] [Full Text] [PDF]

				J. R. Corboy, J. Gault, and B. K. Kleinschmidt-DeMasters An adult case of leukoencephalopathy with intracranial calcifications and cysts Neurology, November 28, 2006; 67(10): 1890 - 1892. [Abstract] [Full Text] [PDF]

				N Revencu and M Vikkula Cerebral cavernous malformation: new molecular and clinical insights J. Med. Genet., September 1, 2006; 43(9): 716 - 721. [Abstract] [Full Text] [PDF]

				B. Guclu, A. K. Ozturk, K. L. Pricola, A. Seker, M. Ozek, and M. Gunel Cerebral Venous Malformations Have Distinct Genetic Origin From Cerebral Cavernous Malformations Stroke, November 1, 2005; 36(11): 2479 - 2480. [Abstract] [Full Text] [PDF]