title: 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 = 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.
authors.affiliation: Medical and Molecular Genetics, Indiana University, School of Medicine, Hereditary Genomics Division, 410 W. 10th St., MI-4000, Indianapolis, IN 46202, USA. tforoud@iupui.edu
authors.forename: N
authors.initials: N
authors.lastname: Pankratz
authors.forename: D K
authors.initials: DK
authors.lastname: Kissell
authors.forename: M W
authors.initials: MW
authors.lastname: Pauciulo
authors.forename: C A
authors.initials: CA
authors.lastname: Halter
authors.forename: A
authors.initials: A
authors.lastname: Rudolph
authors.forename: R F
authors.initials: RF
authors.lastname: Pfeiffer
authors.forename: K S
authors.initials: KS
authors.lastname: Marder
authors.forename: T
authors.initials: T
authors.lastname: Foroud
authors.forename: W C
authors.initials: WC
authors.lastname: Nichols
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D017354:Point Mutation / Q000235:genetics; D012307:Risk Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein