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| Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: Evidence of a common founder across European populations |
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| Author(s): Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M |
| Source: AMERICAN JOURNAL OF HUMAN GENETICS Volume: 76 Issue: 4 Pages: 672-680 Published: APR 2005 |
| Times Cited: 203 References: 36 |
| Abstract: 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Farrer, MJ (reprint author), Mayo Clin, Dept Neurosci, Birdsall Bldg,4500 San Pablo Rd, Jacksonville, FL 32224 USA |
Addresses:
1. Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
2. Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA
3. St Olavs Hosp, Dept Neurol, Trondheim, Norway
4. Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway
5. Royal Victoria Hosp, Dept Neurol, Belfast BT12 6BA, Antrim North Ireland
6. Queens Univ Belfast, Sch Biol & Biochem, Belfast BT7 1NN, Antrim North Ireland
7. Mater Misericordiae Univ Hosp, Dept Neurol, Dublin, Ireland
8. Conway Inst Biomol & Biomed Res, Dublin, Ireland
9. New York State Dept Hlth, Wadsworth Ctr Labs & Res, Albany, NY 12201 USA
10. Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA
11. Mayo Clin, Dept Neurol, Rochester, MN USA
12. Polish Acad Sci, Med Res Ctr, Dept Neurodegenerat Disorders, Warsaw, Poland
13. Minist Spraw Wewnetrznych & Adm Hosp, Dept Neurol, Warsaw, Poland |
| Publisher: UNIV CHICAGO PRESS, 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA |
| Subject Category: Genetics & Heredity |
| IDS Number: 904RS |
| ISSN: 0002-9297 |
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