The applicants propose to clone the gene for cerebral cavernous malformation of the brain (CCM1). Stroke is the third leading cause of death in the US but little is known of its cause. CCM is a rare cause of stroke but may have a population incidence as high as 0.9% in the general population. Little is known of the natural history of CCM. These lesions consist of dilated sinusoidal vascular spaces lined by a single layer of epithelium. CCM is often familial but is more often familial in Hispanic Americans. In Hispanic Americans, particularly Mexican Americans, the disease is nearly always related to a founder effect as shown by haplotype analysis. The applicants propose to take advantage of this founder effect to clone the gene. They have located CCM1 on chromosome 7q with a lod score of 10.6 at zero recombination for D7S657. They have used the founder effect in Hispanic Americans to locate CCM1 by linkage disequilibrium mapping to an interval of approximately 220,000 bp and have a cloned contig of genomic DNA that spans this interval. They will identify the gene and mutation in Hispanic Americans and verify that this is the correct gene by identifying mutations in unrelated non-Hispanic affecteds since about 30% of familial CCM in non-Hispanic kindreds is attributable to mutation in CCM1.
In Specific Aim 2, they will determine the prevalence and spectrum of mutations in the CCM1 gene in familial and sporadic CCM in both normal and disease tissue from patients. They can do this with the disease haplotype before the gene is cloned. When they have cloned the gene, the spectrum of mutations will give some indication of whether these mutations act at the cellular level as gain of function or loss of function mutations.
In Specific Aim 3, they will look at the penetrance of CCM mutations and natural history of disease development. The will extend their kindreds and ascertain a group of gene carriers using the disease haplotype before the gene is cloned or the mutation afterwards. This will allow determination of penetrance. It will also allow prospective studies on unaffected gene carriers to determine the natural history of the disease using imaging studies and clinical examination.
In Specific Aim 4, they will identify a second CCM gene in non-Hispanic patients. They have sufficient family material to carry out this aim in the absence of heterogeneity.
In Specific Aim 5, they will localize the CCM1 gene in normal and disease tissue to elucidate the pathogenesis of CCM. They will determine which cells carrying CCM1 mutations actually cause the CCM lesions. They have established a collection of these lesions and have begun developing cell cultures of different cell lines from lesions in order to pursue this aim.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-NEUC (02))
Program Officer
Marler, John R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
Zip Code
Fu, Chuanhai; Yan, Feng; Wu, Fang et al. (2007) Mitotic phosphorylation of PRC1 at Thr470 is required for PRC1 oligomerization and proper central spindle organization. Cell Res 17:449-57
Durante, P; Cardenas, C G; Whittaker, J A et al. (2004) Low-threshold L-type calcium channels in rat dopamine neurons. J Neurophysiol 91:1450-4
Guzeloglu-Kayisli, Ozlem; Kayisli, Umit A; Amankulor, Nduka M et al. (2004) Krev1 interaction trapped-1/cerebral cavernous malformation-1 protein expression during early angiogenesis. J Neurosurg 100:481-7
Guzeloglu-Kayisli, Ozlem; Amankulor, Nduka M; Voorhees, Jennifer et al. (2004) KRIT1/cerebral cavernous malformation 1 protein localizes to vascular endothelium, astrocytes, and pyramidal cells of the adult human cerebral cortex. Neurosurgery 54:943-9; discussion 949
Laurans, Maxwell S H; DiLuna, Michael L; Shin, Dana et al. (2003) Mutational analysis of 206 families with cavernous malformations. J Neurosurg 99:38-43
Gunel, Murat; Laurans, Maxwell S H; Shin, Dana et al. (2002) KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein. Proc Natl Acad Sci U S A 99:10677-82
Uranishi, R; Baev, N I; Ng, P Y et al. (2001) Expression of endothelial cell angiogenesis receptors in human cerebrovascular malformations. Neurosurgery 48:359-67; discussion 367-8
Wong, J H; Awad, I A; Kim, J H (2000) Ultrastructural pathological features of cerebrovascular malformations: a preliminary report. Neurosurgery 46:1454-9
Baev, N I; Awad, I A (1998) Endothelial cell culture from human cerebral cavernous malformations. Stroke 29:2426-34