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

Jan O. Aasly; Carles Vilariño-Güell; Justus C. Dachsel; Philip J. Webber; Andrew B. West; Kristoffer Haugarvoll; Krisztina K. Johansen; Mathias Toft; John G. Nutt; Haydeh Payami; Jennifer M. Kachergus; Sarah J. Lincoln; Amela Felic; Christian Wider; Alexandra I. Soto-Ortolaza; Stephanie A. Cobb; Linda R. White; Owen A. Ross; Matthew J. Farrer

doi:10.1002/mds.23265

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

Jan O. Aasly, Carles Vilariño-Güell, Justus C. Dachsel, Philip J. Webber, Andrew B. West, Kristoffer Haugarvoll, Krisztina K. Johansen, Mathias Toft, John G. Nutt, Haydeh Payami, Jennifer M. Kachergus, Sarah J. Lincoln, Amela Felic, Christian Wider, Alexandra I. Soto-Ortolaza, Stephanie A. Cobb, Linda R. White, Owen A. Ross, Matthew J. Farrer

Neuroscience

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	2156-2163
Number of pages	8
Journal	Movement Disorders
Volume	25
Issue number	13
DOIs	https://doi.org/10.1002/mds.23265
State	Published - Oct 15 2010

Keywords

Genetic
Kinase
LRRK2
Parkinson's disease

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/mds.23265

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Aasly, J. O., Vilariño-Güell, C., Dachsel, J. C., Webber, P. J., West, A. B., Haugarvoll, K., Johansen, K. K., Toft, M., Nutt, J. G., Payami, H., Kachergus, J. M., Lincoln, S. J., Felic, A., Wider, C., Soto-Ortolaza, A. I., Cobb, S. A., White, L. R., Ross, O. A., & Farrer, M. J. (2010). Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease. Movement Disorders, 25(13), 2156-2163. https://doi.org/10.1002/mds.23265

Aasly, JO, Vilariño-Güell, C, Dachsel, JC, Webber, PJ, West, AB, Haugarvoll, K, Johansen, KK, Toft, M, Nutt, JG, Payami, H, Kachergus, JM, Lincoln, SJ, Felic, A, Wider, C, Soto-Ortolaza, AI, Cobb, SA, White, LR, Ross, OA & Farrer, MJ 2010, 'Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease', Movement Disorders, vol. 25, no. 13, pp. 2156-2163. https://doi.org/10.1002/mds.23265

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title = "Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease",

abstract = "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.",

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AU - Dachsel, Justus C.

AU - Webber, Philip J.

AU - West, Andrew B.

AU - Haugarvoll, Kristoffer

AU - Johansen, Krisztina K.

AU - Toft, Mathias

AU - Nutt, John G.

AU - Payami, Haydeh

AU - Kachergus, Jennifer M.

AU - Lincoln, Sarah J.

AU - Felic, Amela

AU - Wider, Christian

AU - Soto-Ortolaza, Alexandra I.

AU - Cobb, Stephanie A.

AU - White, Linda R.

AU - Ross, Owen A.

AU - Farrer, Matthew J.

PY - 2010/10/15

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N2 - 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.

AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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