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Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia
A Joutel1, C Corpechot, A Ducros
1INSERM U25, Faculté de Medecine Necker-Enfants Malades, Paris, France.
Insights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder causing stroke and dementia. Researchers identified mutations in the Notch3 gene, suggesting it is the cause of CADASIL.
Area of Science:
- Genetics
- Neurology
- Vascular Biology
Background:
- Stroke and vascular dementia are significant health concerns.
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition causing stroke and dementia.
- CADASIL is characterized by recurrent ischemic events, white matter abnormalities, and specific vascular pathology.
Purpose of the Study:
- To identify the genetic basis of CADASIL.
- To investigate the role of the Notch3 gene in the pathogenesis of CADASIL.
Main Methods:
- Gene mapping to chromosome 19.
- Characterization of the human Notch3 gene within the CADASIL critical region.
- Mutation analysis in CADASIL patients.
Main Results:
- The Notch3 gene was localized to the CADASIL critical region.
- Mutations disrupting the Notch3 gene were identified in CADASIL patients.
- Ultrastructural analysis revealed severe alterations in vascular smooth muscle cells.
Conclusions:
- The Notch3 gene is strongly implicated as the causative gene in CADASIL.
- Mutations in Notch3 lead to the characteristic pathology of CADASIL, including stroke and vascular dementia.
- This finding provides a molecular basis for understanding and potentially treating CADASIL.
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 subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. 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.