Mitochondrial DNA sequence variation and mutation rate in patients with CADASIL
Johanna Annunen-Rasila1, Saara Finnilä, Kati Mykkänen
1Department of Neurology, University of Oulu, Oulu, Finland.
Neurogenetics
|June 30, 2006
Summary
Mutations in the NOTCH3 gene causing CADASIL may increase mitochondrial DNA (mtDNA) mutations. This study found increased mtDNA sequence variation in CADASIL patients, suggesting a link between NOTCH3 gene mutations and mtDNA instability.
Area of Science:
- Genetics
- Neurology
- Mitochondrial Biology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukencephalopathy (CADASIL) is caused by NOTCH3 gene mutations.
- CADASIL presents with strokes, cognitive decline, and dementia.
- A prior case linked NOTCH3 mutations with mitochondrial DNA (mtDNA) myopathy.
Purpose of the Study:
- To investigate if NOTCH3 gene mutations predispose mitochondrial DNA (mtDNA) to mutations.
- To analyze nucleotide variation in the mtDNA coding region of CADASIL patients.
Main Methods:
- Examined mtDNA coding region sequences in 20 CADASIL pedigrees (77 patients).
- Utilized conformation-sensitive gel electrophoresis and sequencing.
- Compared mtDNA variation in CADASIL patients with 192 healthy controls.
Main Results:
- Identified 180 mtDNA coding region sequence differences, including novel substitutions.
- Observed differing mtDNA in maternal relatives within two pedigrees.
- Found increased average pairwise mtDNA sequence differences and polymorphisms in CADASIL lineages compared to controls.
Conclusions:
- Mitochondrial DNA (mtDNA) sequence variation is elevated in CADASIL pedigrees.
- These findings suggest a potential relationship between NOTCH3 gene mutations and mtDNA alterations.
