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NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL
M Dichgans1, J Herzog, T Gasser
1Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany. mdichgans@nefo.med.uni-muenchen.de
Insights
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 mutations. A new deletion causing an odd number of cysteine residues supports a unifying molecular hypothesis for CADASIL.
Area of Science:
- Neurology
- Genetics
- Molecular Biology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukencephalopathy (CADASIL) is a hereditary cerebrovascular disorder.
- It is characterized by recurrent strokes and progressive vascular dementia.
- Mutations in the NOTCH3 gene are the known cause of CADASIL.
Purpose of the Study:
- To investigate the molecular mechanisms underlying CADASIL.
- To identify novel mutations in the NOTCH3 gene associated with CADASIL.
- To test the hypothesis that an altered cysteine residue count in EGF-like repeats is critical for CADASIL pathogenesis.
Main Methods:
- Genetic analysis of patients with CADASIL.
- Identification and characterization of NOTCH3 gene mutations.
- Analysis of the impact of mutations on cysteine residue number in EGF-like repeats.
Main Results:
- A novel in-frame deletion in NOTCH3 was identified, leading to the loss of three cysteine residues in EGF repeat 6.
- This mutation results in an odd number of cysteine residues within this specific EGF-like repeat domain.
- Previously identified CADASIL mutations also alter the cysteine count, typically resulting in an odd number.
Conclusions:
- The findings support the hypothesis that an imbalance in cysteine residues (odd number) within NOTCH3 EGF-like repeats is a common critical event in CADASIL.
- This alteration likely leads to unpaired, reactive cysteine residues, contributing to the disease pathology.
- Understanding this unifying molecular mechanism may aid in developing targeted therapies for CADASIL.
Abstract:
Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy causing stroke and vascular dementia. All CADASIL mutations identified so far result in the loss or gain of one cysteine residue within epidermal growth factor (EGF)-like repeat domains. Here an in-frame deletion causing a loss of three cysteine residues within EGF repeat 6 is reported. These data are consistent with the hypothesis that the change toward an odd number of cysteine residues within a given EGF repeat and therefore an unpaired, reactive cysteine residue is the common and critical molecular event in CADASIL.