Comprehensive screening of a North American Parkinson's disease cohort for LRRK2 mutation.
BACKGROUND
Recently, mutations in LRRK2 encoding the protein dardarin have been linked to an autosomal dominant form of parkinsonism.


OBJECTIVE
To identify mutations causing Parkinson's disease (PD) in a cohort of North Americans with familial PD.


METHODS
We sequenced exons 1-51 of LRRK2 in 79 unrelated North American PD patients reporting a family history of the disease.


RESULTS
One patient had a missense mutation (Thr2356Ile) while two others had the common Gly2019Ser mutation. In addition, 1 patient had a 4-bp deletion in close proximity to the exon 19 splice donor (IVS20+4delGTAA) that in vitro abrogates normal splicing.


CONCLUSIONS
Our observations in the 79 North American patients indicate that mutations in LRRK2 are associated with approximately 5% of PD cases with a positive family history. The results also show that G2019S represents approximately half of the LRRK2 mutations in United States PD cases with a family history of the disease. We have identified two novel mutations in LRRK2.
Johnson
Janel
J
Laboratory of Neurogenetics, National Institute on Aging, Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
Paisán-Ruíz
Coro
C
Lopez
Grisel
G
Crews
Cynthia
C
Britton
Angela
A
Malkani
Roniel
R
Evans
E Whitney
EW
McInerney-Leo
Aideen
A
Jain
Shushant
S
Nussbaum
Robert L
RL
Foote
Kelly D
KD
Mandel
Ronald J
RJ
Crawley
Anthony
A
Reimsnider
Sharon
S
Fernandez
Hubert H
HH
Okun
Michael S
MS
Gwinn-Hardy
Katrina
K
Singleton
Andrew B
AB
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D001923:Brain Chemistry / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009656:North America; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics
D005819:Genetic Markers; D022821:RNA Splice Sites; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases