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(Stroke. 2001;32:6.)
© 2001 American Heart Association, Inc.

Expedited Publication

An Animal Model for the Molecular Genetics of CADASIL

Karl J. Fryxell, PhD; Marcus Soderlund, BS Theodor V. Jordan, MS

From the Department of Biology, George Mason University, Fairfax, Va.

Correspondence to Karl J. Fryxell, Department of Biology, MSN 3E1, George Mason University, Fairfax, VA 22030. E-mail kfryxell{at}gmu.edu

Background—CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited condition that causes repeated small-scale strokes in adults. CADASIL is caused only by mutations in the human NOTCH3 gene that increase or decrease the number of cysteines within the epidermal growth factor (EGF) repeats of the NOTCH3 protein. Drosophila lethal-Abruptex is a similar condition because it is also caused only by mutations that increase or decrease the number of cysteines within the EGF repeat portion of the Notch protein.

Summary of Comment—Drosophila lethal-Abruptex and human CADASIL are precisely analogous at the molecular level, and both are genetically dominant. These precise similarities, together with the fact that the structure and function of Notch has been highly conserved throughout the animal kingdom, provide an animal model for the molecular and genetic aspects of human CADASIL. It also provides support for Spinner’s proposal that CADASIL results from dominant inhibition of the Notch pathway.

Conclusions—Because the phenotypes of Notch mutations are cell-autonomous, the symptoms of CADASIL indicate that adult vascular smooth muscle cells require the continuing function of the NOTCH3 pathway in the adult. For this reason, further analysis of the NOTCH3 pathway may provide more general insights into the biology of vascular smooth muscle cells. In the case of CADASIL, the powerful genetic tools available in Drosophila should help to facilitate future research.

Editorial Comment

Joseph M. Verdi, PhD, Guest Editor Christopher J. Kubu, MSc, Guest Editor

Laboratory of Neural Stem Cell Biology, Robarts Research Institute, Department of Physiology, Program in Neuroscience, London, Ontario, Canada

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