Judith Gault, Ph.D.
The Genetics of Cerebral Vascular Malformations

We have recently discovered biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation (CCM) lesion. CCMs are a common genetic disease (0.5% of the population harbors them) predisposing patients to a lifetime risk of hemorrhagic stroke and epilepsy. CCMs represent a unique Mendelian form of both stroke and epilepsy; the pathobiology of this disease provides a paradigm for understanding and modifying a specific vascular phenotype predisposing to stroke and epilepsy.

The somatic and germ line CCM1 mutations provide conclusive evidence that the “two-hit” mechanism, is likely operating in causing this form of stroke and epilepsy. The “two-hit” mechanism has gained prominence in the field of cancer causation and was originally proposed by Dr. Alfred G, Knudson, Jr. to explain the relationship between hereditary and non-hereditary forms of cancer.

The “two-hit” mechanism of CCM lesion genesis has been controversial. The published evidence to date has not been compelling and several distinguished researchers do not believe that the “two-hit” mechanism underlies CCM lesion genesis. In our report, we identify somatic and germ line mutations in the CCM1 gene from a surgically excised CCM lesion. The mutations are on different chromosomes and knock out both copies of the gene in a proportion of cells from the lesion, providing substantial proof of the “two-hit” mechanism.

This novel discovery will expand the role of somatic mutation to diseases other than those related to cancer. Somatic mutations in other CCM genes might well contribute to lesion genesis. Trans-heterozygous mutations (known in polycystic kidney disease) in 2 of the 3 known CCM genes may be associated with CCM lesions, and the substantial clinical variations found in lesion behavior may reflect combinations of different germ line and somatic mutations.

Selected Recent Publications

Browne D.L., Gault J., Thompson M.B., Hauge X.Y., Evans G.A., and Litt M. (1991) Dinucleotide repeat polymorphism at the D11S527 locus. Nucleic Acids Research 19:4790.

Zonana J., Gault J., Davies K.J.P., Jones M., Browne D., Litt M., Brockdorff N., Rastan S., Clarke A., Thomas N.S.T. (1993) Detection of a Molecular Deletion at the DXS732 Locus in a Patient with X-linked Hypohidrotic Ectodermal Dysplasia (EDA), with the Identification of a Unique Junctional Fragment. Am J Hum Genet. 52:78-84.

Thomas, N.S.T., Chelly, J. Zonana, J., Davies, K.J.P., Morgan, S., Gault, J., Rack, K.A., Buckle, V.J., Brockdorff, N., Clarke, A., and Monaco, A. (1993) Characterisation of molecular DNA rearrangements within the Xq12-q13.1 region, in three patients with X-linked hypohidrotic ectodermal dysplasia (EDA). Human Molecular Genetics 2:10.

Zonana, J., Jones M., Clarke A., Gault J., Muller, B., and Thomas N.S.T. (1994) Detection of de novo mutations and analysis of their origin in families with X linked hypohidrotic ectodermal dysplasia. J Med Genet. 31:287-292.

Leonard S., Gault J., Moore T., Hopkins J., Robinson M., Olincy A., Adler L.E., Cloninger R., Kaufmann C.A., Tsuang M.T., Faraone S.V., Malaspina D., Svrakic D.M., Freedman R. (1998) Further investigation of a chromosome 15 locus in schizophrenia: Analysis of affected sibpairs from the NIMH genetics initiative. Am J Med Genet 81:308-312.

Leonard S., Gault J., Adams C., Breese C.R., Rollins Y., Adler L.E., Olincy A., Freedman R. (1998) Nicotinic Receptors, Smoking and Schizophrenia (review article) Restorative Neurology and Neuroscience, 12:195-201.

Gault J., Berger R., Robinson M., Drebing C., Logel J., Hopkins J., Moore T., Jacobs S., Merriwether J., Choi M.J., Kim E.J., Walton K., Buiting K., Davis A., Breese C., Freedman R., Leonard S. (1998) Genomic Organization and Partial Duplication of the Human a7 Neuronal Nicotinic Acetylcholine Receptor Gene (CHRNA7). Genomics 52 (2), 173-185.

Leonard S., Adler L.E., Olincy A., Breese C., Gault J., Ross R.G., Lee M., Cawthra E., Nagamoto H.T., Freedman R. The role of nicotine in psychopathology. A book chapter in “Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities” Wiley-Liss, New York. pp. 305-320, 1998.

Leonard S., Breese C., Adams C., Benhammou K., Gault J., Stevens K., Lee M., Adler L. Olincy A., Ross R., Freedman R. (2000) Smoking and schizophrenia: abnormal nicotinic receptor expression. Eur. J. Pharm. 393:237-242.

Freedman R., Adams C., Adler L.E., Bickford P.C., Gault J., Harris J., Olincy A., Ross R.G., Stevens K., Waldo M., and Leonard S. (2000) An Inhibitory Neurophysiological Deficit as a Phenotype for Genetic Investigation of Schizophrenia. Am. J. Med Gen., Neuropsych Gen. 97:58-64.

Leonard,S., Adler,L.E., Benhammou,K., Berger,R., Breese,C.R., Drebing,C., Gault,J., Lee,M.J., Logel,J., Olincy,A., Ross,R.G., Stevens,K., Sullivan,B., Vianzon,R., Vernich,D.E., Waldo,M., Walton,K., and Freedman,R. (2001). Smoking and mental illness. Pharmacol. Biochem. Behav. 70, 561-570.

Freedman R., Leonard S., Gault J., Hopkins J., Cloninger C.R., Kaufmann C.A., Tsuang M.T., Farone, S.V., Malaspina D., Svrakic D.M., Sanders A., Gejman P. (2001) Linkage Disequilibrium for Schizophrenia at the Chromosome 15q13-14 Locus of the ?7-Nicotinic Acetylcholine Receptor Subunit Gene (CHRNA7). Am J. Med Genet 105:20-22.

Leonard S., Gault J., Hopkins J., Logel J., Vianzon R., Short M., Drebing C., Berger R., Zerbe G., Olincy A., Ross R. G., Adler L.E., Freedman R. (2002) Promoter variants in the a7 nicotinic receptor subunit gene are associated with an inhibitory deficit in schizophrenia. Achieves in General Psychiatry. Arch Gen Psychiatry. 2002 Dec;59(12):1085-96.

Shenkar, R., Elliott, J.P., Diener, K., Gault, J., Hu, L.J., Cohrs, R.J., Phang, T., Hunter, L., Breeze R. E., Awad, I.A. (2003) Differential Gene Expression in Human Cerebral Vascular Malformations. Neurosurgery . 52(2):465-478.

Gault,J., Hopkins,J., Berger,R., Drebing,C., Logel,J., Walton,K., Short,M., Vianzon,R., Olincy,A., Ross,R.G., Adler,L.E., Freedman,R., and Leonard,S. (2003). Comparison of polymorphisms in the a7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects. Am J Med Genet, Neuropsychiatric Genetics. 123B:39-49.

Gault J., Sarin H., Awadallah N.A., Shenkar R., Awad I.A., (2004) Pathobiology of Human Cerebral Vascular Malformations: Basic Mechanisms and Clinical Relevance. Neurosurgery. 55(1): 1-17.
Jabbour P., Gault J., Shenkar R., Awad I.A. (2004) What Genes Can Teach Us About Human Cerebrovascular Malformations. In Clinical Neurosurgery.51:140-52.

Jabbour P., Gault J., Awad, I.A. Molecular Biology Of Cavernous Malformations. In Lanzino G, Spetzler R,(eds): Cavernous Malformations of the Brain and Spinal Cord, 1st edition. New York, Thieme. In Press 2005.

Jabbour P., Gault J., Murk SE, Awad IA, Multiple spinal cavernous malformations with atypical phenotype after prior irradiation case report. Neursurgery. 2004 Dec;55(6):1431.

Shenkar, R., Sarin, H., Awadallah, N., Gault, J., Kleinschmidt-DeMasters, B.K. and Awad, I.A. Variations in structural proteins expression and endothelial cell proliferation in relation to clinical manifestations of cerebral cavernous malformations. Neurosurgery. Neurosurgery. 2005 Feb;56(2):343-54.

Freedman, R., Leonard, S., Waldo, M., Gault, J., Olincy, A., Adler, L.E. “Characterization of Allelic Variants at Chromosome 15q14 in Schizophrenia.” Genes, Brain, and Behavior. In Press 2005.

Gault J., Shenkar R., Recksiek P., Awad I., “Biallelic Somatic and Germ Line CCM1 Truncating Mutations in a Cerebral Cavernous Malformation Lesion” Stroke. Stroke 2005 Feb 17.

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