Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia

Nature volume 383, pages707–710(1996)Cite this article

Abstract

STROKE is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent sub-cortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuro-imaging1,2. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries3. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis4. We have previously mapped the mutant gene to chromosome 19 (ref. 5). Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.

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Affiliations

  1. INSERM U25, Faculté de Médecine Necker-Enfants Malades, 156 rue de Vaugirard, Paris, 75730, France

    Anne Joutel, Christophe Corpechot, Anne Ducros, Philippe Mouton, Sonia Alamowitch, Valérie Domenga, Michaelle Cécillion, Emmanuelle Maréchal, Jacqueline Maciazek, Céline Vayssière, Jean François Bach & Elisabeth Tournier-Lasserve

  2. Service de Neurologie, Hôpital St Antoine, 184 rue du Fbg St Antoine, Paris, 75012, France

    Katayoun Vahedi, Hugues Chabriat & Marie Germaine Bousser

  3. Généthon, 1 rue de 1'internationale, Evry, 91000, France

    Corinne Cruaud & Jean Weissenbach

  4. CHNO des XV-XX, 28 rue de Charenton, Paris, 75571, France

    Emmanuel-Alain Cabanis

  5. Service de Neuropathologie, CH&U de Lille, rue 8 mai 1945, Lille, 59000, France

    Marie Madeleine Ruchoux

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  1. Anne Joutel
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  2. Christophe Corpechot
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  3. Anne Ducros
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  4. Katayoun Vahedi
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  5. Hugues Chabriat
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  6. Philippe Mouton
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  7. Sonia Alamowitch
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  8. Valérie Domenga
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  9. Michaelle Cécillion
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  10. Emmanuelle Maréchal
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  11. Jacqueline Maciazek
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  12. Céline Vayssière
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  13. Corinne Cruaud
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  14. Emmanuel-Alain Cabanis
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  15. Marie Madeleine Ruchoux
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  16. Jean Weissenbach
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  17. Jean François Bach
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  18. Marie Germaine Bousser
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  19. Elisabeth Tournier-Lasserve
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Joutel, A., Corpechot, C., Ducros, A. et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383, 707–710 (1996). https://doi.org/10.1038/383707a0

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