A locus for a dominant form of PD has been mapped to the pericentromeric region of chromosome 12 in a Japanese family. We have confirmed linkage in two families of European ancestry and identified mutations in the gene for LRRK2 in these two and four additional families with dominantly inherited PD. All mutations are located in highly conserved domains of the gene. The LRRK2 protein belongs to the ROCO protein family, and includes a ras domaine (ras of complex proteins) and a protein kinase

more »

... in of the MAPKKK class and several other major functional domains. Within affected carriers of Families A and D, six post-mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology and progressive supranuclear palsy-like pathology. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.