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Human Molecular Genetics Advance Access published online on April 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi171
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received February 19, 2005
Revised April 13, 2005
Accepted April 22, 2005

Article

CADASIL MUTATIONS IMPAIR NOTCH3 GLYCOSYLATION BY FRINGE

Joseph F. Arboleda-Velasquez 1, Raajit Rampal 2, Erik Fung 3, Diane C. Darland 4, Liu M. 5, Maria C. Martinez 1, Christine P. Donahue 1, Manuel F. Navarro-Gonzalez 1, Peter Libby 3, Patricia A. D'Amore 4, Masanori Aikawa 3, Robert S. Haltiwanger 2, and Kenneth S. Kosik 1*

1 Neurology Department, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
2 Department of Biochemistry and Cell Biology. Institute for Cell and Developmental Biology. State University of New York at Stony Brook. Stony Brook, New York, 11794, USA.
3 Leducq Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
4 Schepens Eye Research Institute and the Departments of Ophthalmology and Pathology, Harvard Medical School, 02114, Boston, Massachusetts, USA.
5 Laboratory for Drug Discovery in Neurodegeneration. Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA, USA.

* To whom correspondence should be addressed.
Kenneth S. Kosik, E-mail: kkosik{at}rics.bwh.harvard.edu


  Abstract

Mutations in the Notch3 gene trigger adult onset stroke and vascular dementia in patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). All CADASIL mutations described to date affect the epidermal growth factor-like (EGF-like) repeats located in the extracellular domain of the Notch3 receptor. These domains are also the target of sequential complex O-linked glycosylation mediated by protein O-fucosyltransferase 1 and Fringe. We investigated whether O-fucosylation or Fringe-mediated elongation of O-fucose on Notch3 is impaired by CADASIL mutations. Biochemical studies of a Notch3 fragment containing the first five EGF-like repeats of Notch3, including the mutational hot spot, showed that CADASIL mutations do not affect the addition of O-fucose, but do impair carbohydrate chain elongation by Fringe. CADASIL changes also induced aberrant homodimerization of mutant Notch3 fragments and heterodimerization of mutant Notch3 with Lunatic Fringe itself. Together, these data suggest that Fringe plays a role in CADASIL pathophysiology.


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