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


  • Potential conflict of interest: Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 NS40256). MJF and OAR are supported by the Michael J. Fox Foundation. JOA is supported by the Research Council of Norway. Additional support for ABW was from an NIH R00NS058111 award, for HP from an NIH R01NS36960, and for PJW an American Parkinson's Disease Association fellowship. CVG, JCD, KH, KKJ, MT, JGN, JMK, SJL, AF, CW, AIS, SAC, LRW have no financial disclosures to make.


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