Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients.
OBJECTIVE
Homozygous or compound heterozygous parkin mutations cause juvenile parkinsonism. Heterozygous parkin mutations are also found in patients with typical Parkinson's disease (PD), but it is unclear whether a single "mutation" in a patient is related to disease or is coincidental, because the mutation frequency in control subjects is unknown. We present a comprehensive sequence analysis of parkin in control subjects.


METHODS
A total of 302 patients and 301 control subjects were sequenced, and findings were replicated in 1,260 additional patients and 1,657 control subjects.


RESULTS
Thirty-four variants were detected, of which 21 were novel; 12 were polymorphisms and 22 were rare variants. Patients and control subjects did not differ in the frequency, type, or functional location of the variants. Even P437L, a common mutation thought to be pathogenic, was present in unaffected control subjects.


CONCLUSIONS
parkin point mutations are not exclusive to PD. The mere presence of a single point mutation in a patient, in the absence of a second mutation, should not be taken as a cause of disease unless corroborated by family data and functional studies. This study does not support the notion that heterozygous parkin sequence variants (mutations or polymorphisms) are risk factors for PD. Whether heterozygous dosage anomalies are associated with PD remains to be determined.
Kay
Denise M
DM
Wadsworth Center, New York State Department of Health, Albany, NY 12201-2002, USA.
Moran
Dawn
D
Moses
Lina
L
Poorkaj
Parvoneh
P
Zabetian
Cyrus P
CP
Nutt
John
J
Factor
Stewart A
SA
Yu
Chang-En
CE
Montimurro
Jennifer S
JS
Keefe
Robert G
RG
Schellenberg
Gerard D
GD
Payami
Haydeh
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D017354:Point Mutation; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein