Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease.
OBJECTIVE
To determine the frequency, distribution, and clinical features of Parkinson disease (PD) with PINK1 mutations.


METHODS
Retrospective clinical and genetic review.


METHODS
University hospital.


METHODS
We performed extensive mutation analyses of PINK1 in 414 PD patients negative for parkin mutations (mean [SD] age at onset, 42.8 [14.3] years), including 391 unrelated patients (190 patients with sporadic PD and 201 probands of patients with familial PD) from 13 countries.


RESULTS
We found 10 patients with PD from 9 families with PINK1 mutations and identified 7 novel mutations (2 homozygous mutations [p.D297MfsX22 and p.W437R] and 5 single heterozygous mutations [p.A78V, p.P196QfsX25, p.M342V, p.W437R, and p.N542S]). No compound heterozygous mutations were found. The frequency of homozygous mutations was 4.26% (2 of 47) in families with autosomal recessive PD and 0.53% (1 of 190) in patients with sporadic PD. The frequency of heterozygous mutations was 1.89% (2 of 106) in families with potential autosomal dominant PD and 1.05% (2 of 190) in patients with sporadic PD. The mean (SD) age at onset in patients with single heterozygous mutations (53.6 [11.1] years; range, 39-69 years) was higher than that in patients with homozygous mutations (34.0 [20.3] years; range, 10-55 years). Myocardial iodine-123 metaiodobenzylguanidine uptake was low in patients with heterozygous mutations but not in those with homozygous mutations.


CONCLUSIONS
Our results suggest that homozygous PINK1 mutations tend to be diagnosed as the early-onset autosomal recessive form of PD. Single heterozygous mutations may contribute to the development of sporadic PD and also could be an additional genetic predisposition for developing familial PD. The reduced myocardial iodine-123 metaiodobenzylguanidine uptake observed in patients with single heterozygous PINK1 mutations is similar to that seen in patients with sporadic PD.
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
Ryuya
R
Kumazawa
Hiroyuki
H
Tomiyama
Yuanzhe
Y
Li
Yoko
Y
Imamichi
Manabu
M
Funayama
Hiroyo
H
Yoshino
Fusako
F
Yokochi
Toshihiro
T
Fukusako
Yasushi
Y
Takehisa
Kenichi
K
Kashihara
Tomoyoshi
T
Kondo
Bulent
B
Elibol
Sevasti
S
Bostantjopoulou
Tatsushi
T
Toda
Hirohide
H
Takahashi
Fumihito
F
Yoshii
Yoshikuni
Y
Mizuno
Nobutaka
N
Hattori
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase