Parkin mutation dosage and the phenomenon of anticipation: a molecular genetic study of familial parkinsonism.
BACKGROUND
parkin mutations are a common cause of parkinsonism. Possessing two parkin mutations leads to early-onset parkinsonism, while having one mutation may predispose to late-onset disease. This dosage pattern suggests that some parkin families should exhibit intergenerational variation in age at onset resembling anticipation. A subset of familial PD exhibits anticipation, the cause of which is unknown. The aim of this study was to determine if anticipation was due to parkin mutation dosage.


METHODS
We studied 19 kindreds that had early-onset parkinsonism in the offspring generation, late-onset parkinsonism in the parent generation, and > or = 20 years of anticipation. We also studied 28 early-onset parkinsonism cases without anticipation. Patients were diagnosed by neurologists at a movement disorder clinic. parkin analysis included sequencing and dosage analysis of all 12 exons.


RESULTS
Only one of 19 cases had compound parkin mutations, but contrary to our postulate, the affected relative with late-onset parkinsonism did not have a parkin mutation. In effect, none of the anticipation cases could be attributed to parkin. In contrast, 21% of early-onset parkinsonism patients without anticipation had parkin mutations.


CONCLUSIONS
Anticipation is not linked to parkin, and may signify a distinct disease entity.
Poorkaj
Parvoneh
P
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, USA. pips@u.washington.edu
Moses
Lina
L
Montimurro
Jennifer S
JS
Nutt
John G
JG
Schellenberg
Gerard D
GD
Payami
Haydeh
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020132:Anticipation, Genetic; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
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