International Journal of Advances In Case Reports

MITOCHONDRIAL ABERRATION AND THEIR CONNECTION TO NOTCH 3 GENE MUTATIONS IN CADASIL PATIENTS

Khaled K. Abu-Amero*

abuamero@gmail.com

CADASIL, NOTCH3, Mitochondria, mutation, Arabs.

CADASIL patients with mutations in the NOTCH3 nuclear gene has shown ultrastructural and biochemical abnormalities of the mitochondria in their skeletal muscle biopsies suggesting that Notch signaling pathway may directly or indirectly influences the mitochondrial respiration. In this study five CADASIL patients belonging to five unrelated pedigrees were investigated to detect any mitochondrial abnormalities in their circulating leucocytes which may help to eliminate the need for invasive muscle biopsies. Entire mitochondrial coding region was sequenced in both directions for these CADASIL patients; also their mitochondrial respiratory activity (MRA) in circulating leukocytes was assessed and relative mtDNA content was quantified. The results showed that in comparison with ethnicity matching healthy controls (n=159), mean number of mtDNA sequence variants both synonymous and nonsynonymous in CADASIL patients was not statistically significant (p=0.378). No novel pathologic mitochondrial DNA (mtDNA) mutation(s) were found in the patients after excluding haplogroup specific single nucleotide polymorphisms (SNPs). No significant difference was seen in relative mtDNA content between patients and controls (p=<0.32). Mean MRA depicted a significant decline of 22% in CADASIL patients when compared with ethnicity and demographically matching controls (p= 0.001). In conclusion, this study enforces that hypothesis that Notch3 gene mutation are linked to mitochondrial abnormalities and both act in a synergetic manner to develop CADASIL. The exact mechanism is worth investigating further and may shed light on how neuro-signaling interact with mitochondrial energetic to develop neurological diseases.