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GENATLAS PHENOTYPE
last update : 18-11-2009
Symbol CADASIL
Location 19p13.12
Name cerebral arteriopathy with subcortical infarcts and leukoencephalopathy
Other name(s) dementia, hereditary multi-infarct type
Corresponding gene NOTCH3
Other symbol(s) CASIL
Main clinical features
  • recurrent subcortical infarcts and leukoencephalopathy
  • small vessel disease leading to recurrent ischemic stroke and vascular dementia
    • Genetic determination autosomal dominant
    Related entries . including a variant form with migraine, linked to hemodynamic abnormalities due to smooth muscle cell degeneration
    Function/system disorder cardiovascular
    Type disease
    Gene product
    Name Drosophila Notch homolog 3, mutation gain of function
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    missense   abnormal protein/gain of function addition or removal of cysteines from the EGF-like repeats
    Remark(s) . disease-causing mutations invariably affect cysteine residues within epidermal growth factor-like repeat domains in the extracellular domain of the NOTCH3 receptor (CADASIL-associated mutations significantly enhance multimerization compared with wild-type) (PMID: 19417009))
  • mutant Notch3 is more prone to form aggregates than wild-type, the mutant aggregates are resistant to degradation, leading to their accumulation in the ER, and impairment of ER function caused by the retention of mutant Notch3 is involved in the pathogenesis of CADASIL (cells expressing mutant Notch3 exhibit impaired proliferation and increased sensitivity to proteasome inhibition resulting in cell death) (PMID: 19825845))