Objective: To discover potential penetrance biomarkers in mitochondrial DNA (mtDNA) for Parkin and PINK1 mutation carriers.

Background: Biallelic mutations in Parkin and PINK1 are fully penetrant and cause recessively inherited Parkinson’s disease (PD). On the other hand, heterozygous mutations in these genes may be considered as a risk factor for PD or even act in a dominant manner with highly reduced penetrance. Since both Parkin and PINK1 function in the removal of dysfunctional mitochondria, we hypothesize that mtDNA mutations influence the age-dependent penetrance and thus disease manifestation.

Method: We performed deep mtDNA sequencing in 124 individuals with Illumina NextSeq (>10,000X) in blood-derived DNA and brain tissue-derived DNA from one Parkin carrier to assess mitochondria mutational load including somatic mosaicism and individual mtDNA variants. Patients were recruited from Germany, Italy, Tunisia, Canada, Serbia and comprised carriers of PINK1 (n=32) and Parkin mutations (n=52), idiopathic PD patients (n=20) and controls (n=20). We also compared mtDNA variants between IPSC-derived neurons and post-mortem brain frontal cortex, occipital lobe, and substantia nigra of one patient with Parkin mutations and three controls.

Results: A mean coverage of >10,000X was achieved with high sensitivity of detecting low level heteroplasmic variants (<15% allelic frequency). Using regression models, Parkin mutation carriers have significantly more mtDNA variants including both single nucleotide variants (SNV) and copy number variations (CNV) compared to controls and idiopathic PD, even after adjusting by age. Likewise, PINK1 mutation carriers also have more total SNVs compared to controls. Further investigation into affected specific PINK1/Parkin mutations carriers show an increase in low level heteroplasmic variants compared to unaffected PINK1/Parkin mutation carriers. Lastly, comparing early and late onset Parkin mutation carriers, we identified a potential protective variant in ATP6 (p.A177T).

Conclusion: Parkin and PINK1 mutations may predispose to an increased mitochondrial mutational load. Increased level of heteroplasmic mitochondrial DNA mutations may function as a second hit and partially explain the penetrance in (heterozygous) Parkin/PINK1 mutation carriers.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/deep-mitochondrial-sequencing-in-parkinsons-disease-reveals-possible-genetic-modifiers-of-reduced-penetrance-in-parkin-pink1-mutation-carriers/