Mitochondrial DNA sequence variation and mutation rate in patients with CADASIL

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.

Proteome Analysis of Cultivated Vascular Smooth Muscle Cells from a CADASIL Patient

“…This is consistent with the observations that glutathione depletion resulted in subsequent mitochondrial dysfunction and ROS accumulation (66) and also induced growth inhibition (62). Our findings that mtDNA mutations are more frequent in CADASIL patients (67) and the CADASIL VSMCs used in this study have impaired growth capacity conform to the observations above.…”

Neuromuscular Implications in CADASIL

“…In single cases, CADASIL patients may additionally present with skeletal muscle abnormalities [3]. This was the case in a patient carrying the R133C Notch3 mutation, in whom additionally the novel G5650A mitochondrial DNA (mtDNA) point mutation in the mitochondrial tRNAAla gene was found [5].…”

“…Rarely, CADASIL may also present with dystonia [15] or may go along with abnormalities of the retinal vasculature [16]. In some patients, Notch3 mutations additionally present with neuromuscular symptoms and signs [2,3,4,5,6,7]. In up to 33% of the cases, however, the initial manifestation of CADASIL is migraine [11].…”

“…Clinically, Notch3 mutations manifest as recurrent ischemic strokes, migraine with aura, psychiatric symptoms, cognitive decline, pseudobulbar palsy, or subcortical dementia [3, 11]. Rarely, CADASIL may also present with dystonia [15] or may go along with abnormalities of the retinal vasculature [16].…”

“…After deciding from the abstracts if an article could be useful for the workup of the present topic and if the included patients were confirmed CADASIL cases, appropriate articles were reviewed for neuromuscular involvement in CADASIL. The number of articles finally selected for the actual presentation was 6 [2,3,4,5,6,7]. …”