TY - JOUR
T1 - Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology
AU - Zimprich, Alexander
AU - Biskup, Saskia
AU - Leitner, Petra
AU - Lichtner, Peter
AU - Farrer, Matthew
AU - Lincoln, Sarah
AU - Kachergus, Jennifer
AU - Hulihan, Mary
AU - Uitti, Ryan J.
AU - Calne, Donald B.
AU - Stoessl, A. Jon
AU - Pfeiffer, Ronald F.
AU - Patenge, Nadja
AU - Carbajal, Iria Carballo
AU - Vieregge, Peter
AU - Asmus, Friedrich
AU - Müller-Myhsok, Bertram
AU - Dickson, Dennis W.
AU - Meitinger, Thomas
AU - Strom, Tim M.
AU - Wszolek, Zbigniew K.
AU - Gasser, Thomas
N1 - Funding Information:
The three corresponding authors are equally responsible senior authors. Drs. Gasser and Meitinger led the genetic investigations, and Dr. Wszolek was responsible for the longitudinal clinical study of the large families. We gratefully acknowledge the participation of all patients and family members. The work was funded in part by the German National Genome Network (NGFN; Grant number 01GS0116, German Ministry for Education and Research), the Competence Network Parkinson's disease (German Ministry for Education and Research, Grant number 01Gl0201), the National Institutes of Health, the National Institute of Neurologic Disorders and Stroke, the Morris K. Udall Parkinson's Disease Research Center of Excellence (grant awarded to the Mayo Clinic Jacksonville, P50-NS40256-06), the Canadian Institutes for Health Research, and the Pacific Parkinson's Research Institute. Dr. Y. Tsuboi, Mrs. E. Wszolek, S. Calne, B. Pfeiffer, A. Strongosky, and J. Searcy helped to collect clinical material. Drs. P. McGeer, K. Berry, and R. McComb provided the pathology material for reevaluation, and Dr. Y. Tsuboi assisted in neuropathologic studies.
PY - 2004/11/18
Y1 - 2004/11/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=8844233579&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=8844233579&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2004.11.005
DO - 10.1016/j.neuron.2004.11.005
M3 - Article
C2 - 15541309
AN - SCOPUS:8844233579
SN - 0896-6273
VL - 44
SP - 601
EP - 607
JO - Neuron
JF - Neuron
IS - 4
ER -