Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations

Abstract

Objective: Mutations in both alleles of parkin have been shown to result in Parkinson disease (PD).However, it is unclear whether haploinsufficiency (presence of a mutation in only 1 of the 2 parkin alleles) increases the risk for PD. Methods:We performed comprehensive dosage and sequence analysis of all 12 exons of parkin in a sample of 520 independent patients with familial PD and 263 controls. We evaluated whether presence of a single parkin mutation, either a sequence (point mutation or small insertion/deletion) or dosage (whole exon deletion or duplication) mutation, was found at increased frequency in cases as compared with controls. We then compared the clinical characteristics of cases with 0, 1, or 2 parkin mutations. Results:We identified 55 independent patients with PD with at least 1 parkin mutation and 9 controls with a single sequence mutation. Cases and controls had a similar frequency of single sequence mutations (3.1% vs 3.4%, p ϭ 0.83); however, the cases had a significantly higher rate of dosage mutations (2.6% vs 0%, p ϭ 0.009). Cases with a single dosage mutation were more likely to have an earlier age at onset (50% with onset at Յ45 years) compared with those with no parkin mutations (10%, p ϭ 0.00002); this was not true for cases with only a single sequence mutation (25% with onset at Յ45 years, p ϭ 0.06). Conclusions:Parkin haploinsufficiency, specifically for a dosage mutation rather than a point mutation or small insertion/deletion, is a risk factor for familial PD and may be associated with earlier age at onset. Neurology

A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2

“…[10][11][12][13][14]16,17 However, not all studies found a higher frequency in patients than in controls. 20 Although the sampling of patients varied across studies (early-onset, late-onset, familial PD), the frequency of PARK2 mutations in our patients with PD, when subgrouped to match each study, are generally in line with most prior studies.…”

“…The majority of positive results are heterozygous and difficult for clinicians to interpret because whether having one mutation can cause, increase risk, or accelerate onset of Parkinson disease (PD) is unknown. [9][10][11][12][13][14][15][16][17][18][19][20][21] The second aim of our study was to determine, conclusively, if heterozygous mutations are associated with PD. We designed this study specifically to address this question, and to that end, amassed a large sample size to ensure analytic power, analyzed the coding regions for all types of variations, and importantly, used the same rigorous mutation analysis and validation methods in control subjects as in patients.…”

Olfaction in Parkin heterozygotes and compound heterozygotes

“…The role of Parkin mutation heterozygosity in the pathogenesis of PD is controversial. [14][15][16][17] Data supporting the hypothesis that heterozygous mutations convey a risk for PD include imaging findings [18][19][20] and studies showing an increased frequency of heterozygous carriers in PD cases compared to controls. 15 Our finding of similar olfactory performance in Parkin heterozygotes with PD and noncarriers with PD may be viewed as consistent with the hypothesis that Parkin mutation heterozygosity is not an independent risk factor for PD.…”

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

“…For this reason, more than 200 putative pathogenic mutations have been reported worldwide, affecting numerous ethnic populations [33,35,59,[64][65][66][67][68][69][70][71][72][73][74][75][76][77]. The PARK2 mutation spectrum includes homozygous or compound heterozygous missense and nonsense point mutations, as well as several exon rearrangements (both duplications and deletions) involving all 12 exons and the promoter region.…”

“…Several studies have sought to address this issue, but the findings published so far are inconsistent and conflicting. Some reports indicate that CNVs heterozygous mutations in PARK2 associate with increased PD risk [49,68], albeit others found no differences for an association [33,69]. Not only association studies but also examinations of families have yielded contradictory results.…”