Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations.
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.
Pankratz
N
N
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
Kissell
D K
DK
Pauciulo
M W
MW
Halter
C A
CA
Rudolph
A
A
Pfeiffer
R F
RF
Marder
K S
KS
Foroud
T
T
Nichols
W C
WC
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
D005819:Genetic Markers; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein