Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.
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.
Zimprich
Alexander
A
Department of Neurodegenerative Disease, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
Biskup
Saskia
S
Leitner
Petra
P
Lichtner
Peter
P
Farrer
Matthew
M
Lincoln
Sarah
S
Kachergus
Jennifer
J
Hulihan
Mary
M
Uitti
Ryan J
RJ
Calne
Donald B
DB
Stoessl
A Jon
AJ
Pfeiffer
Ronald F
RF
Patenge
Nadja
N
Carbajal
Iria Carballo
IC
Vieregge
Peter
P
Asmus
Friedrich
F
Müller-Myhsok
Bertram
B
Dickson
Dennis W
DW
Meitinger
Thomas
T
Strom
Tim M
TM
Wszolek
Zbigniew K
ZK
Gasser
Thomas
T
D000328:Adult; D000595:Amino Acid Sequence; D015152:Blotting, Northern; D001921:Brain / Q000473:pathology*; D002874:Chromosome Mapping; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D000090263:Leucine-Rich Repeat Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016631:Lewy Bodies / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000090263:Leucine-Rich Repeat Proteins; D011506:Proteins; D011494:Protein Kinases; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases