The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease: is there a gender effect?
BACKGROUND
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson disease (PD) identified to date, and have been implicated in both familial and sporadic forms of the disease. The G2019S change in LRRK2 exon 41 has been associated with disease at varying frequencies in Asian, European, North American, and North African populations, and is particularly prevalent among Ashkenazi Jews.


METHODS
We assessed the occurrence of the LRRK2 G2019S, I2012T, I2020T, and R1441G/C/H mutations in our cohort of Jewish Israeli patients with PD, and determined the LRRK2 haplotypes in 76 G2019S-carriers detected and in 50 noncarrier Ashkenazi patients, using six microsatellite markers that span the entire gene.


RESULTS
Only the G2019S mutation was identified among our patients with PD, 14.8% in the Ashkenazi and 2.7% in the non-Ashkenazi patients, and in 26% and 10.6% of the Ashkenazi familial and apparently sporadic cases. The carrier frequencies in the Ashkenazi and non-Ashkenazi control samples were 2.4% and 0.4%. A common shared haplotype was detected in all non-Ashkenazi and half-Ashkenazi carriers and in all full-Ashkenazi carriers tested, except two. Women and patients with a positive family history of PD were significantly over-represented among the G2019S mutation carriers. Age at disease onset was similar in carriers and noncarriers.


CONCLUSIONS
Our data suggest that the LRRK2 G2019S mutation plays an important role in the causality of familial and sporadic Parkinson disease (PD) in Israel and that gender affects its frequency among patients. Although testing symptomatic patients may help establish the diagnosis of PD, the value of screening asymptomatic individuals remains questionable until the penetrance and age-dependent risk of this mutation are more accurately assessed, and specific disease prevention or modifying interventions become available.
Orr-Urtreger
A
A
Genetic Institute, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. aviorr@tasmc.health.gov.il
Shifrin
C
C
Rozovski
U
U
Rosner
S
S
Bercovich
D
D
Gurevich
T
T
Yagev-More
H
H
Bar-Shira
A
A
Giladi
N
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007585:Jews / Q000208:ethnology / Q000235:genetics*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000208:ethnology / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D012727:Sex Characteristics; D012737:Sex Factors
D005819:Genetic Markers; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases