Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations.
Autosomal dominant parkinsonism has been attributed to pathogenic amino acid substitutions in leucine-rich repeat kinase 2 (LRRK2). By sequencing multiplex families consistent with a PARK8 assignment, we identified a novel heterozygous LRRK2 mutation. A referral sample of 248 affected probands from families with autosomal dominant parkinsonism was subsequently assessed; 7 (2.8%) were found to carry a heterozygous LRRK2 6055G-->A transition (G2019S). These seven patients originate from the United States, Norway, Ireland, and Poland. In samples of patients with idiopathic Parkinson disease (PD) from the same populations, further screening identified six more patients with LRRK2 G2019S; no mutations were found in matched control individuals. Subsequently, 42 family members of the 13 probands were examined; 22 have an LRRK2 G2019S substitution, 7 with a diagnosis of PD. Of note, all patients share an ancestral haplotype indicative of a common founder, and, within families, LRRK2 G2019S segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years. In summary, our study demonstrates that LRRK2 G2019S accounts for parkinsonism in several families within Europe and North America. Our work highlights the fact that a proportion of clinically typical, late-onset PD cases have a genetic basis.
Kachergus
Jennifer
J
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Mata
Ignacio F
IF
Hulihan
Mary
M
Taylor
Julie P
JP
Lincoln
Sarah
S
Aasly
Jan
J
Gibson
J Mark
JM
Ross
Owen A
OA
Lynch
Timothy
T
Wiley
Joseph
J
Payami
Haydeh
H
Nutt
John
J
Maraganore
Demetrius M
DM
Czyzewski
Krzysztof
K
Styczynska
Maria
M
Wszolek
Zbigniew K
ZK
Farrer
Matthew J
MJ
Toft
Mathias
M
D000367:Age Factors; D000368:Aged; D000595:Amino Acid Sequence; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant; D006801:Humans; D007494:Ireland; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009664:Norway; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D011044:Poland; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014481:United States; D044465:White People / Q000235:genetics
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
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