Yale School of Medicine


Louvi Research, Neurosurgery

Williamson Research, Neurosurgery

P.O., Box 208082
New Haven, CT 06520-8082
Tel: 203.785.2805
Fax: 203.785.6916

Molecular Genetics and Biology of Cavernous Malformations

Besides IA, another major focus of my lab has been the study of molecular genetics and biology of cerebral cavernous malformations (CCM) in collaboration with Angeliki Louvi, PhD.

CCM is a major form of hemorrhagic stroke, affecting nearly 0.5% of the population. CCMs are abnormally dilated vascular channels in the brain that can lead to bleeding or seizures (Fig. 2). Our work over the past 15 years on this disease have lead to several seminal contributions, resulting in over 20 publications in peer-reviewed journals and over 40 national and international presentations. Our findings range from localization of the first gene that causes CCM to 7q (PNAS 1995 92(14):6620-4) to the demonstration of a single disease-causing mutation in Hispanic-Americans (N Engl J Med. 1996 ;334(15):946-51) to large scalemutational analysis of CCM genes (J Neurosurg 2003; 99(1):38-43) to molecular biological work molecules aimed at understanding their biological function (Fig. 3) (PNAS 2002; 99(16):10677-82 , Neurosurg 2004; 54(4):943-9, Stroke 2006; 37(2):518-23, Neurosurg 62(4):930-8, 2008 , Stroke 2008 in press). This body of work spanning the past 15 years, is representative of our general philosophy of identification of disease genes followed by the dissection of disease biology. This work now places us in a unique position, for the first time, to attempt to develop novel therapies for CCM.

Fig. 2: MRI imaging of CCM. A. Sagittal & B. Coronal MR images of a large CCM (arrowhead) that caused a gross hemorrhage (white arrows) in a child. C. & D. Axial images of the brain with the genetic form of CCM reveals multiple small hypointense lesions due to old blood products (hemosiderin) (arrows). E. & F. Axial images show a typical venous malformation with multiple enlarged vessels (arrows). This patient previously underwent successful surgery for removal of and associated CCM.

Fig. 3: CCM3/PDCD10 protein expression in the human brain is strong in arterial endothelium (a) and in the cytoplasm of large pyramidal neurons (b, arrows) but is weak or absent from cortical venous endothelium (b, arrowhead). Similar protein expression intensity is seen in the cerebellum (c, d; higher magnification) with staining observed in vessels (arrow) and neurons (arrowheads). From Neurosurg 62(4):930-8, 2008

This work is currently funded by a R01 from NINDS/NIH.