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      Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.

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          Abstract

          We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain 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. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.

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          Author and article information

          Journal
          Neuron
          Neuron
          Elsevier BV
          0896-6273
          0896-6273
          Nov 18 2004
          : 44
          : 4
          Affiliations
          [1 ] Department of Neurodegenerative Disease, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
          Article
          S0896627304007202
          10.1016/j.neuron.2004.11.005
          15541309
          e0c16400-1e9f-4c93-88f5-93a98008bb3e
          History

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