Mt4216C variant in linkage with the mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction resulting in an increased risk of Parkinson's disease in the Irish

Northern Ireland Regional Histocompatibility and Immunogenetics Laboratory, Blood Transfusion Building, City Hospital, Belfast BT9 7TS, Northern Ireland, UK.
Experimental Gerontology (Impact Factor: 3.49). 05/2003; 38(4):397-405. DOI: 10.1016/S0531-5565(02)00266-8
Source: PubMed


Polymorphism of the mtDNA genome has been implicated as playing a role in the development and pathogenesis of Parkinson's disease (PD). A PCR-RFLP methodology was employed to generate genetic haplotypes for a cohort of 90 PD sufferers. No association was observed between the various mtDNA haplotypes observed and PD in comparison to healthy aged controls. The longevity-associated European J haplogroup and T haplogroup were identified and were both found to be in tight linkage with the mt4216C polymorphism. The mt4216C variant was observed at a significantly increased frequency in the PD cases (28%) in comparison to the healthy aged controls (15%; p=0.014). However, when the frequency of the mt4216C variant was examined in a cohort of 200 young controls (18-45 years) a similar frequency to the PD cases (25%) was observed. The frequencies obtained for the two branches of the J haplogroup (J1 and J2) and the T haplogroup in the cohort of PD subjects also reflected those observed for the young controls used in the previous longevity study. These findings lead one to postulate that the mt4216C variant, in linkage with the mtDNA TJ cluster, may influence mitochondrial dysfunction, resulting in an increased risk of PD.

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Available from: Owen A Ross, Jan 17, 2014
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    • "We can predict that a subset of mtDNA mutations influence the functional properties of mitochondria in terms of maximal catalytic capacities of electron transport system (ETS, complexes I-IV) enzymes. Studies on humans have demonstrated that specific mtDNA mutations are associated with increased longevity (Niemi et al. 2003; Ross et al. 2003; Dato et al. 2004), neurodegenerative disease susceptibility (Wallace 1994; Torroni et al. 1997; Ross et al. 2003; van der Walt et al. 2003), sperm motility (Ruiz-Pesini et al. 2000; Montiel-Sosa et al. 2006), sprint performance (Niemi and Majamaa 2005), and possibly climate adaptation (Ruiz-Pesini et al. 2004; Wallace 2005; 2010; Amo and Brand 2007). Moreover, multiple naturally occurring genetic mtDNA variants in different species that have been discovered over the last few years are associated with susceptibility to certain complex disorders, or with tissue-specific alteration in mitochondrial activity (Moreno-Loshuertos et al. 2006). "
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    • "In seeking a possible explanation for these varied findings, Ruiz-Pesini et al. 2004, suggested that the clustering of J mitochondrial haplogroups in colder northern European climes might track with an evolutionary advantage relating to improved mitochondrial energy and therefore heat production, but at the price of increased anti-oxidant stress and the predilection for degenerative diseases in unfavourable cellular environments. Alongside the evidence relating the J mitochondrial haplogroup with longevity, J and related haplogroups have conversely also been variously associated with degenerative diseases including Parkinsons disease (Ross et al. 2003; Mancuso et al. 2007). Additionally, the mitochondrial haplogroups are implicated in clinical manifestations related to atherosclerosis or hypertension (Rosa et al. 2008; Rybka et al. 2011a). "
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    • "Similarly to disease-causing mutations, multiple studies support the functionality of mtDNA genetic variants. Firstly, mtDNA genetic backgrounds (haplogroups) have been repeatedly associated with altered susceptibility to various complex phenotypes including Parkinson's disease [51] [52] [53] [54] [55] [56], type 2 diabetes and its complications [57] [58] [59] [60], endurance athletics [61] [62] [63], various cardiovascular disorders [64–67], age-related macular degeneration [68–70], altered plasma lipid and cholesterol levels [71–73], schizophrenia [74,75], various types of cancer [76–78], human sperm motility [79–81], and successful aging [82–86]. It is worth noting that the high population divergence of mtDNA [87], and its close interplay with nDNA-encoded and environmental factors have resulted in the questioning of some of these associations [88] [89] [90]. "
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