Frequency of loss of function variants in LRRK2 in Parkinson disease

Blauwendraat C.; Reed X.; Kia D.A.; Gan-Or Z.; Lesage S.; Pihlstrøm 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.; Simón-Sánchez 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.; Bouça-Machado R.; Coelho M.; Rosa M.M.; Tolosa E.; Fernandez R.; Ezquerra M.; Marti M.J.; Krüger R.; May P.; Glaab E.; Balling R.; Agid Y.; Anheim M.; Bonnet A.-M.; Borg M.; Broussolle E.; Damier P.; Destée A.; Dürr A.; Durif F.; Krack P.; Klebe S.; Lohmann E.; Martinez M.; Penet C.; Pollak P.; Rascol O.; Tison F.; Tranchant C.; Vérin 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.; Botía J.A.; Clarimón J.; Pastor P.; Zimprich A.; Pihlstrom L.; Koks S.; Taba P.

Frequency of loss of function variants in LRRK2 in Parkinson disease

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 enhance...

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Detalhes bibliográficos
Autores:	Blauwendraat C.; Reed X.; Kia D.A.; Gan-Or Z.; Lesage S.; Pihlstrøm 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.; Simón-Sánchez 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.; Bouça-Machado R.; Coelho M.; Rosa M.M.; Tolosa E.; Fernandez R.; Ezquerra M.; Marti M.J.; Krüger R.; May P.; Glaab E.; Balling R.; Agid Y.; Anheim M.; Bonnet A.-M.; Borg M.; Broussolle E.; Damier P.; Destée A.; Dürr A.; Durif F.; Krack P.; Klebe S.; Lohmann E.; Martinez M.; Penet C.; Pollak P.; Rascol O.; Tison F.; Tranchant C.; Vérin 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.; Botía J.A.; Clarimón J.; Pastor P.; Zimprich A.; Pihlstrom L.; Koks S.; Taba P.
Tipo de documento:	Artigo
Estado:	Published version
Data de publicação:	2018
País:	España
Recursos:	Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositório:	r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:	oai:iibsantpau.fundanetsuite.com:p10172
Acesso em linha:	https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10172 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248108
Nível de acesso:	Acesso aberto
Palavra-chave:	leucine rich repeat kinase 2 LRRK1 protein, human LRRK2 protein, human protein serine threonine kinase adult aged Article case control study cohort analysis confidence interval controlled study female gene gene frequency gene identification genetic association heterozygote human human cell information processing loss of function mutation LRRK1 gene LRRK2 gene lymphoblastoid cell line major clinical study male middle aged next generation sequencing odds ratio Parkinson disease pathophysiology priority journal very elderly DNA sequence genetics high throughput sequencing procedures whole exome sequencing Case-Control Studies Cohort Studies High-Throughput Nucleotide Sequencing Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Loss of Function Mutation Parkinson Disease Protein-Serine-Threonine Kinases Sequence Analysis, DNA Whole Exome Sequencing

Descrição
Resumo:	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 LRRK2 LOF variants contribute to the risk of developing PD. DESIGN, SETTING, AND PARTICIPANTS To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (>23 000 individuals) was analyzed for LOF variants in LRRK1 and LRRK2. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. MAIN OUTCOMES AND MEASURES Frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls. RESULTS Among 11 095 cases with PD and 12 615 controls, LRRK1 LOF variants were identified in 0.205%of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95%CI, 0.45-4.44; P = .49) and LRRK2 LOF variants were found in 0.117%of cases and 0.087%of controls (odds ratio, 1.48; SE, 0.431; 95%CI, 0.63-3.50; P = .36). All association tests suggested lack of association between LRRK1 or LRRK2 variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. CONCLUSIONS AND RELEVANCE Together these findings indicate that haploinsufficiency of LRRK1 or LRRK2 is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in PD. © 2018 American Medical Association. All rights reserved.

Frequency of loss of function variants in LRRK2 in Parkinson disease

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