Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries.
We screened LRRK2 mutations in exon 41 in 904 parkin-negative Parkinson's disease (PD) patients (868 probands) from 18 countries across 5 continents. We found three heterozygous missense (novel I2012T, G2019S, and I2020T) mutations in LRRK2 exon 41. We identified 11 (1.3%) among 868 PD probands, including 2 sporadic cases and 8 (6.2%) of 130 autosomal dominant PD families. The LRRK2 mutations in exon 41 exhibited relatively common and worldwide distribution. Among the three mutations in exon 41, it has been reported that Caucasian patients with G2019S mutation have a single-founder effect. In the present study, Japanese patients with G2019S were unlikely to have a single founder from the Caucasian patients. In contrast, I2020T mutation has a single-founder effect in Japanese patients. Clinically, patients with LRRK2 mutations had typical idiopathic PD. Notably, several patients developed dementia and psychosis, and one with I2020T had low cardiac (123)I-metaiodobenzylguanidine (MIBG) heart/mediastinum ratio, although the ratio was not low in other patients with I2020T or G2019S. Clinical phenotypes including psychosis, dementia, and MIBG ratios are also heterogeneous, similar to neuropathology, in PD associated with LRRK2 mutations.
Tomiyama
Hiroyuki
H
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
Li
Yuanzhe
Y
Funayama
Manabu
M
Hasegawa
Kazuko
K
Yoshino
Hiroyo
H
Kubo
Shin-Ichiro
S
Sato
Kenichi
K
Hattori
Tatsuya
T
Lu
Chin-Song
CS
Inzelberg
Rivka
R
Djaldetti
Ruth
R
Melamed
Eldad
E
Amouri
Rim
R
Gouider-Khouja
Neziha
N
Hentati
Faycal
F
Hatano
Yasuko
Y
Wang
Mei
M
Imamichi
Yoko
Y
Mizoguchi
Koichi
K
Miyajima
Hiroaki
H
Obata
Fumiya
F
Toda
Tatsushi
T
Farrer
Matthew J
MJ
Mizuno
Yoshikuni
Y
Hattori
Nobutaka
N
D000978:Antiparkinson Agents / Q000627:therapeutic use; D005091:Exons; D005190:Family; D005260:Female; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000523:psychology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D000978:Antiparkinson Agents; D007980:Levodopa; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases