Frequency of loss of function variants in LRRK2 in Parkinson disease
- Blauwendraat C.
- Reed X.
- Kia D. A.
- Gan-Or Z.
- Lesage S.
- Pihlstrom L.
- Guerreiro R.
- Gibbs J. R.
- Sabir M.
- Ahmed S.
- Ding J.
- Alcalay R. N.
- Hassin-Baer S.
- Pittman A. M.
- Brooks J.
- Edsall C.
- Hernandez D. G.
- Chung S. J.
- Goldwurm S.
- Toft M.
- Schulte C.
- Bras J.
- Wood N. W.
- Brice A.
- Morris H. R.
- Scholz S. W.
- Nalls M. A.
- Singleton A. B.
- Cookson M. R.
- Gasser T.
- Sharma M.
- Simon-Sanchez J.
- Heutink P.
- Giri A.
- Brockmann K.
- Oertel W.
- Klein C.
- Mohamed F.
- Malard L.
- Elbaz A.
- Corti O.
- Drouet V.
- Corvol J. -C.
- Tesei S.
- Canesi M.
- Valente E. M.
- Petrucci S.
- Ginevrino M.
- Aasly J.
- Houlden H.
- Hardy J.
- Orr-Urtreger A.
- Giladi N.
- Ferreira J.
- Guedes L. C.
- Bouca-Machado R.
- Coelho M.
- Rosa M. M.
- Tolosa E.
- Fernandez R.
- Ezquerra M.
- Marti M. J.
- Kruger R.
- May P.
- Glaab E.
- Balling R.
- Agid Y.
- Anheim M.
- Bonnet A. -M.
- Borg M.
- Broussolle E.
- Damier P.
- Destee A.
- Durr A.
- Durif F.
- Krack P.
- Klebe S.
- Lohmann E.
- Martinez M.
- Penet C.
- Pollak P.
- Rascol O.
- Tison F.
- Tranchant C.
- Verin M.
- Viallet F.
- Vidailhet M.
- Noyce A. J.
- Kaiyrzhanov R.
- Middlehurst B.
- Tan M.
- Plun-Favreau H.
- Holmans P.
- Trabzuni D.
- Quinn J.
- Mok K. Y.
- Kinghorn K. J.
- Billingsley K.
- Lewis P.
- Lovering R.
- R'Bibo L.
- Manzoni C.
- Rizig M.
- Ryten M.
- Guelfi S.
- Escott-Price V.
- Chelban V.
- Foltynie T.
- Williams N.
- Shashakin C.
- Zharkinbekova N.
- Zholdybayeva E.
- Aitkulova A.
- Danjou F.
- Rizzu P.
- Bandres-Ciga S.
- Craig D. W.
- Faghri F.
- Van Keuren-Jensen K.
- Shulman J. M.
- Leonard H. L.
- Robak L.
- Lubbe S.
- Finkbeiner S.
- Mencacci N. E.
- Lungu C.
- Rouleau G. A.
- Van Hilten J. J.
- Marinus J.
- Botia J. A.
- Clarimon J.
- Pastor P.
- Zimprich A.
- Pihlstrom L.
- Koks S.
- Taba P.
DOIAbstract
IMPORTANCE Pathogenic variants in LRRK2 are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated. LRRK2 variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of Lrrk2 and its homologue Lrrk1 results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in LRRK2 increase or decrease the risk of PD. OBJECTIVE To determine whether LRRK1 and LR...
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