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Human Molecular Genetics Advance Access originally published online on April 27, 2005
Human Molecular Genetics 2005 14(12):1631-1639; doi:10.1093/hmg/ddi171
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

CADASIL mutations impair Notch3 glycosylation by Fringe

Joseph F. Arboleda-Velasquez1,{dagger}, Raajit Rampal3,{dagger}, Erik Fung2, Diane C. Darland4, Min Liu5, Maria C. Martinez1, Christine P. Donahue1, Manuel F. Navarro-Gonzalez1, Peter Libby2, Patricia A. D'Amore4, Masanori Aikawa2, Robert S. Haltiwanger3 and Kenneth S. Kosik1,*

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

* To whom correspondence should be addressed at current address: Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-5060, USA. Email: kosik{at}lifesci.ucsb.edu

Received February 19, 2005; Revised April 13, 2005; Accepted April 22, 2005

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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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