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

Neurology. 2009 Jul 28;73(4):279-86. doi: 10.1212/WNL.0b013e3181af7a33.

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 = 0.83); however, the cases had a significantly higher rate of dosage mutations (2.6% vs 0%, p = 0.009). Cases with a single dosage mutation were more likely to have an earlier age at onset (50% with onset at < or =45 years) compared with those with no parkin mutations (10%, p = 0.00002); this was not true for cases with only a single sequence mutation (25% with onset at < or =45 years, p = 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Base Sequence / genetics
  • DNA Mutational Analysis
  • Female
  • Gene Deletion
  • Gene Dosage / genetics*
  • Gene Frequency / genetics
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Genotype
  • Haplotypes / genetics
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism*
  • Parkinson Disease / physiopathology
  • Point Mutation / genetics
  • Risk Factors
  • Ubiquitin-Protein Ligases / genetics*
  • Young Adult

Substances

  • Genetic Markers
  • Ubiquitin-Protein Ligases
  • parkin protein