Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease

Abstract

BackgroundMitochondrial function is impaired in Parkinson's disease (PD) and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA) from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to the risk of PD.MethodsWe examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168 multiplex PD families in which the proband and one parent were diagnosed with PD. 2-tailed Fisher Exact Tests and McNemar's tests were used to compare allele frequencies, and a t-test to compare ages of onset.ResultsThe frequency of affected mothers of the proband with PD (83/167, 49.4%) was not significantly different from the frequency of affected females of the proband generation (115/259, 44.4%) (Odds Ratio 1.22; 95%CI 0.83 - 1.81). After correcting for multiple tests, there were no significant differences in the frequencies of mitochondrial haplogroups or of the 10398G complex I gene polymorphism in PD patients compared to controls, and no significant associations with age of onset of PD. Mitochondrial haplogroup and 10398G polymorphism frequencies were similar in probands having an affected father as compared to probands having an affected mother.ConclusionsThese data fail to demonstrate a bias towards maternal inheritance in familial PD. Consistent with this, we find no association of common haplogroup-defining mtDNA variants or for the 10398G variant with the risk of PD. However, these data do not exclude a role for mtDNA variants in other populations, and it remains possible that other inherited mitochondrial DNA variants, or somatic mDNA mutations, contribute to the risk of familial PD.

Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination

“…Haplogroups were defined based on previously grouped mitochondrial SNPs in European populations 21 (see table 1). …”

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

“…For example, an A4336G transition in the mtDNA tRNA (Gln) gene has been found to be over-represented in PD subjects in some but not other studies (78,118,122,139). More recently, one large study found that a common nt10398G change is underrepresented in PD subjects, but a second study did not (123,151). A G5460A transition was found in one study to associate with PD, but this was not seen in other cohorts (62,122,139).…”

“…2). Most initial attempts to demonstrate a genetic basis for the PD complex I defect were sequence based and either negative or, if positive, not supported through replication (62,118,122,123,139). The first durable data to strongly make a case for mitochondrial DNA (mtDNA) as an important idiopathic PD mediator come not from sequence based studies, but rather from studies of cytoplasmic hybrids, or ''cybrids'' (130).…”

POLG1-Related and other “Mitochondrial Parkinsonisms”: an Overview

“…Overall, despite some negative studies (Latsoudis et al 2008), mtDNA haplogroups have been associated with a number of different neurodegenerative diseases, but to date, the only disease consistently associated with a different mtDNA haplogroup frequency is PD (Mancuso et al 2008a). However, recent data failed to demonstrate a bias towards maternal inheritance in familial PD (Simon et al 2010).…”