Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease

Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestatio...

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Published in:Movement disorders 2010-10, Vol.25 (13), p.2156-2163
Main Authors: Aasly, Jan O., Vilariño-Güell, Carles, Dachsel, Justus C., Webber, Philip J., West, Andrew B., Haugarvoll, Kristoffer, Johansen, Krisztina K., Toft, Mathias, Nutt, John G., Payami, Haydeh, Kachergus, Jennifer M., Lincoln, Sarah J., Felic, Amela, Wider, Christian, Soto-Ortolaza, Alexandra I., Cobb, Stephanie A., White, Linda R., Ross, Owen A., Farrer, Matthew J.
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Asparagine - genetics
Biological and medical sciences
Cell Line, Transformed
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Female
genetic
Genetic Testing
Guanosine Triphosphate - metabolism
Histidine - genetics
Humans
kinase
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
LRRK2
Male
Medical sciences
Middle Aged
Mutation - genetics
Neurology
Norway
Parkinson Disease - diagnosis
Parkinson Disease - genetics
Parkinson's disease
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Psychiatric Status Rating Scales
Tomography, Emission-Computed, Single-Photon - methods
Transfection - methods
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Summary:Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2‐linked parkinsonism. © 2010 Movement Disorder Society
ISSN:0885-3185
1531-8257
DOI:10.1002/mds.23265