S tudy of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration
ABSTRACT Background Mutations in the leucine‐rich repeat kinase 2 gene ( LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers. Methods To estimate the frequency of pathogenic LRRK2 mutations an...
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Published in | Movement disorders Vol. 32; no. 1; pp. 115 - 123 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.01.2017
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Online Access | Get full text |
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Summary: | ABSTRACT
Background
Mutations in the leucine‐rich repeat kinase 2 gene (
LRRK2)
are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of
LRRK2
mutation carriers.
Methods
To estimate the frequency of pathogenic
LRRK2
mutations and to evaluate the association of common
LRRK2
variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic. Sanger sequencing of
LRRK2
exons 30, 31, 35, and 41 was performed in all patients, and genotyping of all 17 known exonic variants with minor allele frequency >0.5% was performed in patients and controls.
Results
LRRK2
mutational screening identified 2 known pathogenic mutations (p.G2019S and p.R1441C), each in 1 PSP patient, the novel p.A1413T mutation in a PSP patient and the rare p.R1707K mutation in a corticobasal degeneration patient. Both p.A1413T and p.R1707K mutations were predicted damaging by at least 2 of 3 prediction programs and affect evolutionary conserved sites of
LRRK2
. Association analysis using common
LRRK2
variants only showed nominal association of the p.L153L variant with PSP.
Conclusions
Our study confirms the presence of pathogenic and potentially pathogenic
LRRK2
mutations in pathologically confirmed primary tauopathies, albeit with low frequency. In contrast to PD, common
LRRK2
variants do not appear to play a major role in determining PSP and corticobasal degeneration risk. © 2016 International Parkinson and Movement Disorder Society. |
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ISSN: | 0885-3185 1531-8257 |
DOI: | 10.1002/mds.26815 |