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Author(s): Zimprich A; Biskup S; Leitner P; Lichtner P; Farrer M; Lincoln S; Kachergus J; Hulihan M; Uitti RJ; Calne DB; Stoessl AJ; Pfeiffer RF; Patenge N; Carbajal IC; Vieregge P; Asmus F; Muller-Myhsok B; Dickson DW; Meitinger T; Strom TM; Wszolek ZK; Gasser T
Title: Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology
Source: NEURON 44 (4): 601-607
Date: 2004 NOV 18
Document Type: Journal : Article
DOI:
Language: English
Comment:
Address: GSF, Natl Res Ctr Environm & Hlth, Inst Human Genet, D-85764 Neuherberg, Germany.
Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, D-72076 Tubingen, Germany. Med Univ Vienna, Dept Neurol, A-1090 Vienna, Austria. Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. Univ British Columbia, Pacific Parkinsons Res Ctr, Vancouver, BC V6T 2B5, Canada. Univ Tennessee, Hlth Sci Ctr, Dept Neurol, Memphis, TN 38103 USA. Klinikum Lemgo, Dept Neurol, D-32657 Lemgo, Germany. Max Planck Inst Psychiat, Computat Genet Grp, D-80804 Munich, Germany. Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany. Reprint: Meitinger, T, GSF, Natl Res Ctr Environm & Hlth, Inst Human Genet, D-
85764 Neuherberg, Germany. E-mail: meitinger@gsf.de
wszolek.zbigniew@mayo.edu thomas.gasser@med.uni-tuebingen.de Author Keywords:
KeyWords Plus: ALPHA-SYNUCLEIN; TAU-SYNUCLEIN; DISEASE; LOCUS; GENE; PROTEIN;
DEGENERATION; LINKAGE; REPEAT; MAPS
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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