Published Online
on February 17, 2005

A more recent version of this article appeared on April 1, 2005

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Submitted on November 26, 2004
Revised on December 16, 2004
Accepted on December 17, 2004

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

Judith Gault PhD^*; Robert Shenkar PhD; Peter Recksiek BS; and Issam A. Awad MD

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.

^* To whom correspondence should be addressed. 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

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