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.
Insights
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.
Abstract:
Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is clinically characterised by recurrent ischemic strokes, migraine with aura, psychiatric symptoms, cognitive decline and dementia. We have previously described a patient with CADASIL caused by a R133C mutation in the NOTCH3 gene and with a concomitant myopathy caused by a 5650G>A mutation in the MTTA gene in mitochondrial DNA (mtDNA). We assume that the co-occurrence of the two mutations is not coincidental and that mutations in the NOTCH3 gene may predispose the mtDNA to mutations. We therefore examined the nucleotide variation in the mtDNA coding region sequences in 20 CADASIL pedigrees with 77 affected patients by conformation-sensitive gel electrophoresis and sequencing. The sequence variation in mtDNA was then compared with that among 192 healthy Finns. A total of 180 mtDNA coding region sequence differences were found relative to the revised Cambridge reference sequence, including five novel synonymous substitutions, two novel nonsynonymous substitutions and one novel tRNA substitution. We found that maternal relatives in two pedigrees differed from each other in their mtDNA. Furthermore, the average number of pairwise differences in sequences from the 41 unrelated maternal lineages with CADASIL was higher than that expected among haplogroup-matched controls. The numbers of polymorphic sites and polymorphisms that were present in only one sequence were also higher among the CADASIL sequences than among the control sequences. Our results show that mtDNA sequence variation is increased within CADASIL pedigrees. These findings suggest a relationship between NOTCH3 and mtDNA.
