Novel Pathogenic LRRK2 p.Asn1437His Substitution in Familial Parkinson's Disease

作者：Aasly Jan O; Vilarino Gueell 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^*

来源：Movement Disorders, 2010, 25(13): 2156-2163.

DOI：10.1002/mds.23265

• LRRK2
• Parkinson's disease
• genetic
• kinase

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 5 3.15, theta = 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.

• 出版日期2010-10-15