TY - JOUR
T1 - Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism
T2 - Evidence of a common founder across European populations
AU - Kachergus, Jennifer
AU - Mata, Ignacio F.
AU - Hulihan, Mary
AU - Taylor, Julie P.
AU - Lincoln, Sarah
AU - Aasly, Jan
AU - Gibson, J. Mark
AU - Ross, Owen A.
AU - Lynch, Timothy
AU - Wiley, Joseph
AU - Payami, Haydeh
AU - Nutt, John
AU - Maraganore, Demetrius M.
AU - Czyzewski, Krzysztof
AU - Styczynska, Maria
AU - Wszolek, Zbigniew K.
AU - Farrer, Matthew J.
AU - Toft, Mathias
N1 - Funding Information:
The authors gratefully thank the patients and families for their participation in this study. Mayo Clinic Jacksonville is an M. K. Udall Parkinson’s Disease Research Center of Excellence (National Institute of Neurological Disorders and Stroke grant P01 NS40256); the authors thank all collaborators from the Udall Center. This study was also supported by National Institute of Aging grant R01 AG022579, National Institutes of Health grant R01 NS36960, Research Council of Norway grant 153487/V50, the Unger-Vetlesen Medical Fund, the Sigurd K. Thoresen Foundation, and the Research and Development Office, Health and Personal Social Services, Northern Ireland.
PY - 2005/4
Y1 - 2005/4
N2 - 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 PARX8 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 LRKK2 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 LRKK2 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.
AB - 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 PARX8 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 LRKK2 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 LRKK2 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.
UR - http://www.scopus.com/inward/record.url?scp=20144387207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20144387207&partnerID=8YFLogxK
U2 - 10.1086/429256
DO - 10.1086/429256
M3 - Article
C2 - 15726496
AN - SCOPUS:20144387207
SN - 0002-9297
VL - 76
SP - 672
EP - 680
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -