Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

Suzanne Lesage; Valérie Drouet; Elisa Majounie; Vincent Deramecourt; Maxime Jacoupy; Aude Nicolas; Florence Cormier-Dequaire; Sidi Mohamed Hassoun; Claire Pujol; Sorana Ciura; Zoi Erpapazoglou; Tatiana Usenko; Claude Alain Maurage; Mourad Sahbatou; Stefan Liebau; Jinhui Ding; Basar Bilgic; Murat Emre; Nihan Erginel-Unaltuna; Gamze Guven; François Tison; Christine Tranchant; Marie Vidailhet; Jean Christophe Corvol; Paul Krack; Anne Louise Leutenegger; Michael A. Nalls; Dena G. Hernandez; Peter Heutink; J. Raphael Gibbs; John Hardy; Nicholas W. Wood; Thomas Gasser; Alexandra Durr; Jean François Deleuze; Meriem Tazir; Alain Destée; Ebba Lohmann; Edor Kabashi; Andrew Singleton; Olga Corti; Alexis Brice; François Tison; Marie Vidailhet; Jean Christophe Corvol; Yves Agid; Mathieu Anheim; Anne Marie Bonnet; Michel Borg; Emmanuel Broussolle; Philippe Damier; Alain Destée; Alexandra Dürr; Franck Durif; Paul Krack; Stephan Klebe; Ebba Lohmann; Maria Martinez; Pierre Pollak; Olivier Rascol; Christine Tranchant; Marc Vérin; François Viallet; Suzanne Lesage; Elisa Majounie; François Tison; Marie Vidailhet; Jean Christophe Corvol; Michael A. Nalls; Dena G. Hernandez; J. Raphael Gibbs; Alexandra Dürr; Sampath Arepalli; Roger A. Barker; Yoav Ben-Shlomo; Daniela Berg; Francesco Bettella; Kailash Bhatia; Rob M.A. de Bie; Alessandro Biffi; Bastiaan R. Bloem; Zoltan Bochdanovits; Michael Bonin; Jose M. Bras; Kathrin Brockmann; Janet Brooks; David J. Burn; Gavin Charlesworth; Honglei Chen; Patrick F. Chinnery; Sean Chong; Carl E. Clarke; Mark R. Cookson; Carl Counsell; Philippe Damier; Jean François Dartigues; Panos Deloukas; Günther Deuschl; David T. Dexter; Karin D. van Dijk; Allissa Dillman; Jing Dong; Frank Durif; Sarah Edkins; Valentina Escott-Price; Jonathan R. Evans; Thomas Foltynie; Jianjun Gao; Michelle Gardner; Alison Goate; Emma Gray; Rita Guerreiro; Clare Harris; Jacobus J. van Hilten; Albert Hofman; Albert Hollenbeck; Peter Holmans; Janice Holton; Michèle Hu; Xuemei Huang; Heiko Huber; Gavin Hudson; Sarah E. Hunt; Johanna Huttenlocher; Thomas Illig; Pálmi V. Jónsson; Laura L. Kilarski; Iris E. Jansen; Jean Charles Lambert; Cordelia Langford; Andrew Lees; Peter Lichtner; Patricia Limousin; Grisel Lopez; Delia Lorenz; Steven Lubbe; Codrin Lungu; María Martinez; Walter Mätzler; Alisdair McNeill; Catriona Moorby; Matthew Moore; Karen E. Morrison; Ese Mudanohwo; Sean S. O’sullivan; Michael J. Owen; Justin Pearson; Joel S. Perlmutter; Hjörvar Pétursson; Vincent Plagnol; Pierre Pollak; Bart Post; Simon Potter; Bernard Ravina; Tamas Revesz; Olaf Riess; Fernando Rivadeneira; Patrizia Rizzu; Mina Ryten; Mohamad Saad; Javier Simón-Sánchez; Stephen Sawcer; Anthony Schapira; Hans Scheffer; Claudia Schulte; Manu Sharma; Karen Shaw; Una Marie Sheerin; Ira Shoulson; Joshua Shulman; Ellen Sidransky; Chris C.A. Spencer; Hreinn Stefánsson; Kári Stefánsson; Joanna D. Stockton; Amy Strange; Kevin Talbot; Carlie M. Tanner; Avazeh Tashakkori-Ghanbaria; Daniah Trabzuni; Bryan J. Traynor; André G. Uitterlinden; Daan Velseboer; Robert Walker; Bart van de Warrenburg; Mirdhu Wickremaratchi; Caroline H. Williams-Gray; Sophie Winder-Rhodes; Isabel Wurster; Nigel Williams; Huw R. Morris; Peter Heutink; John Hardy; Nicholas W. Wood; Thomas Gasser; Andrew B. Singleton; Alexis Brice

doi:10.1016/j.ajhg.2016.01.014

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

Suzanne Lesage, Valérie Drouet, Elisa Majounie, Vincent Deramecourt, Maxime Jacoupy, Aude Nicolas, Florence Cormier-Dequaire, Sidi Mohamed Hassoun, Claire Pujol, Sorana Ciura, Zoi Erpapazoglou, Tatiana Usenko, Claude Alain Maurage, Mourad Sahbatou, Stefan Liebau, Jinhui Ding, Basar Bilgic, Murat Emre, Nihan Erginel-Unaltuna, Gamze GuvenFrançois Tison, Christine Tranchant, Marie Vidailhet, Jean Christophe Corvol, Paul Krack, Anne Louise Leutenegger, Michael A. Nalls, Dena G. Hernandez, Peter Heutink, J. Raphael Gibbs, John Hardy, Nicholas W. Wood, Thomas Gasser, Alexandra Durr, Jean François Deleuze, Meriem Tazir, Alain Destée, Ebba Lohmann, Edor Kabashi, Andrew Singleton, Olga Corti, Alexis Brice, François Tison, Marie Vidailhet, Jean Christophe Corvol, Yves Agid, Mathieu Anheim, Anne Marie Bonnet, Michel Borg, Emmanuel Broussolle, Philippe Damier, Alain Destée, Alexandra Dürr, Franck Durif, Paul Krack, Stephan Klebe, Ebba Lohmann, Maria Martinez, Pierre Pollak, Olivier Rascol, Christine Tranchant, Marc Vérin, François Viallet, Suzanne Lesage, Elisa Majounie, François Tison, Marie Vidailhet, Jean Christophe Corvol, Michael A. Nalls, Dena G. Hernandez, J. Raphael Gibbs, Alexandra Dürr, Sampath Arepalli, Roger A. Barker, Yoav Ben-Shlomo, Daniela Berg, Francesco Bettella, Kailash Bhatia, Rob M.A. de Bie, Alessandro Biffi, Bastiaan R. Bloem, Zoltan Bochdanovits, Michael Bonin, Jose M. Bras, Kathrin Brockmann, Janet Brooks, David J. Burn, Gavin Charlesworth, Honglei Chen, Patrick F. Chinnery, Sean Chong, Carl E. Clarke, Mark R. Cookson, Carl Counsell, Philippe Damier, Jean François Dartigues, Panos Deloukas, Günther Deuschl, David T. Dexter, Karin D. van Dijk, Allissa Dillman, Jing Dong, Frank Durif, Sarah Edkins, Valentina Escott-Price, Jonathan R. Evans, Thomas Foltynie, Jianjun Gao, Michelle Gardner, Alison Goate, Emma Gray, Rita Guerreiro, Clare Harris, Jacobus J. van Hilten, Albert Hofman, Albert Hollenbeck, Peter Holmans, Janice Holton, Michèle Hu, Xuemei Huang, Heiko Huber, Gavin Hudson, Sarah E. Hunt, Johanna Huttenlocher, Thomas Illig, Pálmi V. Jónsson, Laura L. Kilarski, Iris E. Jansen, Jean Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Steven Lubbe, Codrin Lungu, María Martinez, Walter Mätzler, Alisdair McNeill, Catriona Moorby, Matthew Moore, Karen E. Morrison, Ese Mudanohwo, Sean S. O’sullivan, Michael J. Owen, Justin Pearson, Joel S. Perlmutter, Hjörvar Pétursson, Vincent Plagnol, Pierre Pollak, Bart Post, Simon Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Mohamad Saad, Javier Simón-Sánchez, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Claudia Schulte, Manu Sharma, Karen Shaw, Una Marie Sheerin, Ira Shoulson, Joshua Shulman, Ellen Sidransky, Chris C.A. Spencer, Hreinn Stefánsson, Kári Stefánsson, Joanna D. Stockton, Amy Strange, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, Daniah Trabzuni, Bryan J. Traynor, André G. Uitterlinden, Daan Velseboer, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Isabel Wurster, Nigel Williams, Huw R. Morris, Peter Heutink, John Hardy, Nicholas W. Wood, Thomas Gasser, Andrew B. Singleton, Alexis Brice

Research output: Contribution to journal › Article › peer-review

246 Scopus citations

Abstract

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

Original language	English
Pages (from-to)	500-513
Number of pages	14
Journal	American journal of human genetics
Volume	98
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2016.01.014
State	Published - Mar 3 2016

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10.1016/j.ajhg.2016.01.014

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Lesage, S., Drouet, V., Majounie, E., Deramecourt, V., Jacoupy, M., Nicolas, A., Cormier-Dequaire, F., Hassoun, S. M., Pujol, C., Ciura, S., Erpapazoglou, Z., Usenko, T., Maurage, C. A., Sahbatou, M., Liebau, S., Ding, J., Bilgic, B., Emre, M., Erginel-Unaltuna, N., ... Brice, A. (2016). Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. American journal of human genetics, 98(3), 500-513. https://doi.org/10.1016/j.ajhg.2016.01.014

@article{64f391c79ea041c1a7a7c5d9cff20453,

title = "Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy",

abstract = "Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.",

author = "Suzanne Lesage and Val{\'e}rie Drouet and Elisa Majounie and Vincent Deramecourt and Maxime Jacoupy and Aude Nicolas and Florence Cormier-Dequaire and Hassoun, {Sidi Mohamed} and Claire Pujol and Sorana Ciura and Zoi Erpapazoglou and Tatiana Usenko and Maurage, {Claude Alain} and Mourad Sahbatou and Stefan Liebau and Jinhui Ding and Basar Bilgic and Murat Emre and Nihan Erginel-Unaltuna and Gamze Guven and Fran{\c c}ois Tison and Christine Tranchant and Marie Vidailhet and Corvol, {Jean Christophe} and Paul Krack and Leutenegger, {Anne Louise} and Nalls, {Michael A.} and Hernandez, {Dena G.} and Peter Heutink and Gibbs, {J. Raphael} and John Hardy and Wood, {Nicholas W.} and Thomas Gasser and Alexandra Durr and Deleuze, {Jean Fran{\c c}ois} and Meriem Tazir and Alain Dest{\'e}e and Ebba Lohmann and Edor Kabashi and Andrew Singleton and Olga Corti and Alexis Brice and Fran{\c c}ois Tison and Marie Vidailhet and Corvol, {Jean Christophe} and Yves Agid and Mathieu Anheim and Bonnet, {Anne Marie} and Michel Borg and Emmanuel Broussolle and Philippe Damier and Alain Dest{\'e}e and Alexandra D{\"u}rr and Franck Durif and Paul Krack and Stephan Klebe and Ebba Lohmann and Maria Martinez and Pierre Pollak and Olivier Rascol and Christine Tranchant and Marc V{\'e}rin and Fran{\c c}ois Viallet and Suzanne Lesage and Elisa Majounie and Fran{\c c}ois Tison and Marie Vidailhet and Corvol, {Jean Christophe} and Nalls, {Michael A.} and Hernandez, {Dena G.} and Gibbs, {J. Raphael} and Alexandra D{\"u}rr and Sampath Arepalli and Barker, {Roger A.} and Yoav Ben-Shlomo and Daniela Berg and Francesco Bettella and Kailash Bhatia and {de Bie}, {Rob M.A.} and Alessandro Biffi and Bloem, {Bastiaan R.} and Zoltan Bochdanovits and Michael Bonin and Bras, {Jose M.} and Kathrin Brockmann and Janet Brooks and Burn, {David J.} and Gavin Charlesworth and Honglei Chen and Chinnery, {Patrick F.} and Sean Chong and Clarke, {Carl E.} and Cookson, {Mark R.} and Carl Counsell and Philippe Damier and Dartigues, {Jean Fran{\c c}ois} and Panos Deloukas and G{\"u}nther Deuschl and Dexter, {David T.} and {van Dijk}, {Karin D.} and Allissa Dillman and Jing Dong and Frank Durif and Sarah Edkins and Valentina Escott-Price and Evans, {Jonathan R.} and Thomas Foltynie and Jianjun Gao and Michelle Gardner and Alison Goate and Emma Gray and Rita Guerreiro and Clare Harris and {van Hilten}, {Jacobus J.} and Albert Hofman and Albert Hollenbeck and Peter Holmans and Janice Holton and Mich{\`e}le Hu and Xuemei Huang and Heiko Huber and Gavin Hudson and Hunt, {Sarah E.} and Johanna Huttenlocher and Thomas Illig and J{\'o}nsson, {P{\'a}lmi V.} and Kilarski, {Laura L.} and Jansen, {Iris E.} and Lambert, {Jean Charles} and Cordelia Langford and Andrew Lees and Peter Lichtner and Patricia Limousin and Grisel Lopez and Delia Lorenz and Steven Lubbe and Codrin Lungu and Mar{\'i}a Martinez and Walter M{\"a}tzler and Alisdair McNeill and Catriona Moorby and Matthew Moore and Morrison, {Karen E.} and Ese Mudanohwo and O{\textquoteright}sullivan, {Sean S.} and Owen, {Michael J.} and Justin Pearson and Perlmutter, {Joel S.} and Hj{\"o}rvar P{\'e}tursson and Vincent Plagnol and Pierre Pollak and Bart Post and Simon Potter and Bernard Ravina and Tamas Revesz and Olaf Riess and Fernando Rivadeneira and Patrizia Rizzu and Mina Ryten and Mohamad Saad and Javier Sim{\'o}n-S{\'a}nchez and Stephen Sawcer and Anthony Schapira and Hans Scheffer and Claudia Schulte and Manu Sharma and Karen Shaw and Sheerin, {Una Marie} and Ira Shoulson and Joshua Shulman and Ellen Sidransky and Spencer, {Chris C.A.} and Hreinn Stef{\'a}nsson and K{\'a}ri Stef{\'a}nsson and Stockton, {Joanna D.} and Amy Strange and Kevin Talbot and Tanner, {Carlie M.} and Avazeh Tashakkori-Ghanbaria and Daniah Trabzuni and Traynor, {Bryan J.} and Uitterlinden, {Andr{\'e} G.} and Daan Velseboer and Robert Walker and Warrenburg, {Bart van de} and Mirdhu Wickremaratchi and Williams-Gray, {Caroline H.} and Sophie Winder-Rhodes and Isabel Wurster and Nigel Williams and Morris, {Huw R.} and Peter Heutink and John Hardy and Wood, {Nicholas W.} and Thomas Gasser and Singleton, {Andrew B.} and Alexis Brice",

note = "Funding Information: The authors are grateful to the families for their participation in this study. We thank Merle Ruberg for critical reading of the manuscript, the DNA and Cell Bank of ICM, the Plate-Forme d{\textquoteright}Imagerie Cellulaire de la Piti{\'e}-Salp{\^e}tri{\`e}re (PICPS), and Ebru {\"O}zer and Meltem Pak for sample preparation. We are grateful to the Lille brain bank for the gift of a brain (“Lille Neurobank,” BB-0033-00030). This study was supported by the National Research Funding Agency (ANR-08-NEUR-004-01) in association with ERA-NET NEURON, the France-Parkinson Association, the Roger de Spoelberch Foundation (R12123DD), the French Academy of Sciences, the French program “Investissements d{\textquoteright}avenir” (ANR-10-IAIHU-06), and the European Joint Programme - Neurodegenerative Disease Research (JPND-COURAGE-PD) project. This study was also supported by the Intramural Research Program of the National Institute on Aging and the National Institutes of Neurological Disorders and Stroke, NIH, Department of Health and Human Services (project Z01 AG000958 and by MRC Grant G1100643/1), by the European Social Fund, and by the Ministry of Science, Research, and the Arts, Baden-W{\"u}rttemberg. This work was also supported by the Department of Defense, including grant 10064005/11348001, the French Health Ministry (PHRC), France Parkinson Association, Lille University Hospital (A. Dest{\'e}e), the Atip/Avenir from the National Institute of Health and Medical Research (INSERM), the ANR in association with the ERA-NET E-rare program, the France Alzheimer Association, and a Career Integration Grant from Marie Curie Actions (E.K.). C.P. received a postdoctoral fellowship from the Cognacq-Jay Foundation. S.C. received postdoctoral fellowships from EMBO and AFM-Telethon. Funding Information: The authors are grateful to the families for their participation in this study.We thank Merle Ruberg for critical reading of the manuscript, the DNA and Cell Bank of ICM, the Plate-Forme d''Imagerie Cellulaire de la Piti{\'e}-Salp{\^e}tri{\`e}re (PICPS), and Ebru {\"O} zer and Meltem Pak for sample preparation.We are grateful to the Lille brain bank for the gift of a brain ({"}Lille Neurobank,{"} BB-0033-00030). This study was supported by the National Research Funding Agency (ANR-08-NEUR-004-01) in association with ERA-NET NEURON, the France-Parkinson Association, the Roger de Spoelberch Foundation (R12123DD), the French Academy of Sciences, the French program {"}Investissements d''avenir{"} (ANR-10-IAIHU-06), and the European Joint Programme-Neurodegenerative Disease Research (JPND-COURAGE-PD) project. This study was also supported by the Intramural ResearchProgram of the National Institute on Aging and the National Institutes of Neurological Disorders and Stroke, NIH, Department of Health and Human Services (project Z01 AG000958 and by MRC Grant G1100643/1), by the European Social Fund, and by the Ministry of Science, Research, and the Arts, Baden-W{\"u}rttemberg. This work was also supported by the Department of Defense, including grant 10064005/11348001, the French Health Ministry (PHRC), France Parkinson Association, Lille University Hospital (A. Deste{\'e}), the Atip/Avenir from the National Institute of Health and Medical Research (INSERM), the ANR in association with the ERA-NET E-rare program, the France Alzheimer Association, and a Career Integration Grant from Marie Curie Actions (E.K.). C.P. received a postdoctoral fellowship from the Cognacq-Jay Foundation. S.C. received postdoctoral fellowships from EMBO and AFM-Telethon. Publisher Copyright: {\textcopyright} 2016 The American Society of Human Genetics.",

year = "2016",

month = mar,

day = "3",

doi = "10.1016/j.ajhg.2016.01.014",

language = "English",

volume = "98",

pages = "500--513",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

number = "3",

}

Lesage, S, Drouet, V, Majounie, E, Deramecourt, V, Jacoupy, M, Nicolas, A, Cormier-Dequaire, F, Hassoun, SM, Pujol, C, Ciura, S, Erpapazoglou, Z, Usenko, T, Maurage, CA, Sahbatou, M, Liebau, S, Ding, J, Bilgic, B, Emre, M, Erginel-Unaltuna, N, Guven, G, Tison, F, Tranchant, C, Vidailhet, M, Corvol, JC, Krack, P, Leutenegger, AL, Nalls, MA, Hernandez, DG, Heutink, P, Gibbs, JR, Hardy, J, Wood, NW, Gasser, T, Durr, A, Deleuze, JF, Tazir, M, Destée, A, Lohmann, E, Kabashi, E, Singleton, A, Corti, O, Brice, A, Tison, F, Vidailhet, M, Corvol, JC, Agid, Y, Anheim, M, Bonnet, AM, Borg, M, Broussolle, E, Damier, P, Destée, A, Dürr, A, Durif, F, Krack, P, Klebe, S, Lohmann, E, Martinez, M, Pollak, P, Rascol, O, Tranchant, C, Vérin, M, Viallet, F, Lesage, S, Majounie, E, Tison, F, Vidailhet, M, Corvol, JC, Nalls, MA, Hernandez, DG, Gibbs, JR, Dürr, A, Arepalli, S, Barker, RA, Ben-Shlomo, Y, Berg, D, Bettella, F, Bhatia, K, de Bie, RMA, Biffi, A, Bloem, BR, Bochdanovits, Z, Bonin, M, Bras, JM, Brockmann, K, Brooks, J, Burn, DJ, Charlesworth, G, Chen, H, Chinnery, PF, Chong, S, Clarke, CE, Cookson, MR, Counsell, C, Damier, P, Dartigues, JF, Deloukas, P, Deuschl, G, Dexter, DT, van Dijk, KD, Dillman, A, Dong, J, Durif, F, Edkins, S, Escott-Price, V, Evans, JR, Foltynie, T, Gao, J, Gardner, M, Goate, A, Gray, E, Guerreiro, R, Harris, C, van Hilten, JJ, Hofman, A, Hollenbeck, A, Holmans, P, Holton, J, Hu, M, Huang, X, Huber, H, Hudson, G, Hunt, SE, Huttenlocher, J, Illig, T, Jónsson, PV, Kilarski, LL, Jansen, IE, Lambert, JC, Langford, C, Lees, A, Lichtner, P, Limousin, P, Lopez, G, Lorenz, D, Lubbe, S, Lungu, C, Martinez, M, Mätzler, W, McNeill, A, Moorby, C, Moore, M, Morrison, KE, Mudanohwo, E, O’sullivan, SS, Owen, MJ, Pearson, J, Perlmutter, JS, Pétursson, H, Plagnol, V, Pollak, P, Post, B, Potter, S, Ravina, B, Revesz, T, Riess, O, Rivadeneira, F, Rizzu, P, Ryten, M, Saad, M, Simón-Sánchez, J, Sawcer, S, Schapira, A, Scheffer, H, Schulte, C, Sharma, M, Shaw, K, Sheerin, UM, Shoulson, I, Shulman, J, Sidransky, E, Spencer, CCA, Stefánsson, H, Stefánsson, K, Stockton, JD, Strange, A, Talbot, K, Tanner, CM, Tashakkori-Ghanbaria, A, Trabzuni, D, Traynor, BJ, Uitterlinden, AG, Velseboer, D, Walker, R, Warrenburg, BVD, Wickremaratchi, M, Williams-Gray, CH, Winder-Rhodes, S, Wurster, I, Williams, N, Morris, HR, Heutink, P, Hardy, J, Wood, NW, Gasser, T, Singleton, AB & Brice, A 2016, 'Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy', American journal of human genetics, vol. 98, no. 3, pp. 500-513. https://doi.org/10.1016/j.ajhg.2016.01.014

TY - JOUR

T1 - Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

AU - Lesage, Suzanne

AU - Drouet, Valérie

AU - Majounie, Elisa

AU - Deramecourt, Vincent

AU - Jacoupy, Maxime

AU - Nicolas, Aude

AU - Cormier-Dequaire, Florence

AU - Hassoun, Sidi Mohamed

AU - Pujol, Claire

AU - Ciura, Sorana

AU - Erpapazoglou, Zoi

AU - Usenko, Tatiana

AU - Maurage, Claude Alain

AU - Sahbatou, Mourad

AU - Liebau, Stefan

AU - Ding, Jinhui

AU - Bilgic, Basar

AU - Emre, Murat

AU - Erginel-Unaltuna, Nihan

AU - Guven, Gamze

AU - Tison, François

AU - Tranchant, Christine

AU - Vidailhet, Marie

AU - Corvol, Jean Christophe

AU - Krack, Paul

AU - Leutenegger, Anne Louise

AU - Nalls, Michael A.

AU - Hernandez, Dena G.

AU - Heutink, Peter

AU - Gibbs, J. Raphael

AU - Hardy, John

AU - Wood, Nicholas W.

AU - Gasser, Thomas

AU - Durr, Alexandra

AU - Deleuze, Jean François

AU - Tazir, Meriem

AU - Destée, Alain

AU - Lohmann, Ebba

AU - Kabashi, Edor

AU - Singleton, Andrew

AU - Corti, Olga

AU - Brice, Alexis

AU - Tison, François

AU - Vidailhet, Marie

AU - Corvol, Jean Christophe

AU - Agid, Yves

AU - Anheim, Mathieu

AU - Bonnet, Anne Marie

AU - Borg, Michel

AU - Broussolle, Emmanuel

AU - Damier, Philippe

AU - Destée, Alain

AU - Dürr, Alexandra

AU - Durif, Franck

AU - Krack, Paul

AU - Klebe, Stephan

AU - Lohmann, Ebba

AU - Martinez, Maria

AU - Pollak, Pierre

AU - Rascol, Olivier

AU - Tranchant, Christine

AU - Vérin, Marc

AU - Viallet, François

AU - Lesage, Suzanne

AU - Majounie, Elisa

AU - Tison, François

AU - Vidailhet, Marie

AU - Corvol, Jean Christophe

AU - Nalls, Michael A.

AU - Hernandez, Dena G.

AU - Gibbs, J. Raphael

AU - Dürr, Alexandra

AU - Arepalli, Sampath

AU - Barker, Roger A.

AU - Ben-Shlomo, Yoav

AU - Berg, Daniela

AU - Bettella, Francesco

AU - Bhatia, Kailash

AU - de Bie, Rob M.A.

AU - Biffi, Alessandro

AU - Bloem, Bastiaan R.

AU - Bochdanovits, Zoltan

AU - Bonin, Michael

AU - Bras, Jose M.

AU - Brockmann, Kathrin

AU - Brooks, Janet

AU - Burn, David J.

AU - Charlesworth, Gavin

AU - Chen, Honglei

AU - Chinnery, Patrick F.

AU - Chong, Sean

AU - Clarke, Carl E.

AU - Cookson, Mark R.

AU - Counsell, Carl

AU - Damier, Philippe

AU - Dartigues, Jean François

AU - Deloukas, Panos

AU - Deuschl, Günther

AU - Dexter, David T.

AU - van Dijk, Karin D.

AU - Dillman, Allissa

AU - Dong, Jing

AU - Durif, Frank

AU - Edkins, Sarah

AU - Escott-Price, Valentina

AU - Evans, Jonathan R.

AU - Foltynie, Thomas

AU - Gao, Jianjun

AU - Gardner, Michelle

AU - Goate, Alison

AU - Gray, Emma

AU - Guerreiro, Rita

AU - Harris, Clare

AU - van Hilten, Jacobus J.

AU - Hofman, Albert

AU - Hollenbeck, Albert

AU - Holmans, Peter

AU - Holton, Janice

AU - Hu, Michèle

AU - Huang, Xuemei

AU - Huber, Heiko

AU - Hudson, Gavin

AU - Hunt, Sarah E.

AU - Huttenlocher, Johanna

AU - Illig, Thomas

AU - Jónsson, Pálmi V.

AU - Kilarski, Laura L.

AU - Jansen, Iris E.

AU - Lambert, Jean Charles

AU - Langford, Cordelia

AU - Lees, Andrew

AU - Lichtner, Peter

AU - Limousin, Patricia

AU - Lopez, Grisel

AU - Lorenz, Delia

AU - Lubbe, Steven

AU - Lungu, Codrin

AU - Martinez, María

AU - Mätzler, Walter

AU - McNeill, Alisdair

AU - Moorby, Catriona

AU - Moore, Matthew

AU - Morrison, Karen E.

AU - Mudanohwo, Ese

AU - O’sullivan, Sean S.

AU - Owen, Michael J.

AU - Pearson, Justin

AU - Perlmutter, Joel S.

AU - Pétursson, Hjörvar

AU - Plagnol, Vincent

AU - Pollak, Pierre

AU - Post, Bart

AU - Potter, Simon

AU - Ravina, Bernard

AU - Revesz, Tamas

AU - Riess, Olaf

AU - Rivadeneira, Fernando

AU - Rizzu, Patrizia

AU - Ryten, Mina

AU - Saad, Mohamad

AU - Simón-Sánchez, Javier

AU - Sawcer, Stephen

AU - Schapira, Anthony

AU - Scheffer, Hans

AU - Schulte, Claudia

AU - Sharma, Manu

AU - Shaw, Karen

AU - Sheerin, Una Marie

AU - Shoulson, Ira

AU - Shulman, Joshua

AU - Sidransky, Ellen

AU - Spencer, Chris C.A.

AU - Stefánsson, Hreinn

AU - Stefánsson, Kári

AU - Stockton, Joanna D.

AU - Strange, Amy

AU - Talbot, Kevin

AU - Tanner, Carlie M.

AU - Tashakkori-Ghanbaria, Avazeh

AU - Trabzuni, Daniah

AU - Traynor, Bryan J.

AU - Uitterlinden, André G.

AU - Velseboer, Daan

AU - Walker, Robert

AU - Warrenburg, Bart van de

AU - Wickremaratchi, Mirdhu

AU - Williams-Gray, Caroline H.

AU - Winder-Rhodes, Sophie

AU - Wurster, Isabel

AU - Williams, Nigel

AU - Morris, Huw R.

AU - Heutink, Peter

AU - Hardy, John

AU - Wood, Nicholas W.

AU - Gasser, Thomas

AU - Singleton, Andrew B.

AU - Brice, Alexis

N1 - Funding Information: The authors are grateful to the families for their participation in this study. We thank Merle Ruberg for critical reading of the manuscript, the DNA and Cell Bank of ICM, the Plate-Forme d’Imagerie Cellulaire de la Pitié-Salpêtrière (PICPS), and Ebru Özer and Meltem Pak for sample preparation. We are grateful to the Lille brain bank for the gift of a brain (“Lille Neurobank,” BB-0033-00030). This study was supported by the National Research Funding Agency (ANR-08-NEUR-004-01) in association with ERA-NET NEURON, the France-Parkinson Association, the Roger de Spoelberch Foundation (R12123DD), the French Academy of Sciences, the French program “Investissements d’avenir” (ANR-10-IAIHU-06), and the European Joint Programme - Neurodegenerative Disease Research (JPND-COURAGE-PD) project. This study was also supported by the Intramural Research Program of the National Institute on Aging and the National Institutes of Neurological Disorders and Stroke, NIH, Department of Health and Human Services (project Z01 AG000958 and by MRC Grant G1100643/1), by the European Social Fund, and by the Ministry of Science, Research, and the Arts, Baden-Württemberg. This work was also supported by the Department of Defense, including grant 10064005/11348001, the French Health Ministry (PHRC), France Parkinson Association, Lille University Hospital (A. Destée), the Atip/Avenir from the National Institute of Health and Medical Research (INSERM), the ANR in association with the ERA-NET E-rare program, the France Alzheimer Association, and a Career Integration Grant from Marie Curie Actions (E.K.). C.P. received a postdoctoral fellowship from the Cognacq-Jay Foundation. S.C. received postdoctoral fellowships from EMBO and AFM-Telethon. Funding Information: The authors are grateful to the families for their participation in this study.We thank Merle Ruberg for critical reading of the manuscript, the DNA and Cell Bank of ICM, the Plate-Forme d''Imagerie Cellulaire de la Pitié-Salpêtrière (PICPS), and Ebru Ö zer and Meltem Pak for sample preparation.We are grateful to the Lille brain bank for the gift of a brain ("Lille Neurobank," BB-0033-00030). This study was supported by the National Research Funding Agency (ANR-08-NEUR-004-01) in association with ERA-NET NEURON, the France-Parkinson Association, the Roger de Spoelberch Foundation (R12123DD), the French Academy of Sciences, the French program "Investissements d''avenir" (ANR-10-IAIHU-06), and the European Joint Programme-Neurodegenerative Disease Research (JPND-COURAGE-PD) project. This study was also supported by the Intramural ResearchProgram of the National Institute on Aging and the National Institutes of Neurological Disorders and Stroke, NIH, Department of Health and Human Services (project Z01 AG000958 and by MRC Grant G1100643/1), by the European Social Fund, and by the Ministry of Science, Research, and the Arts, Baden-Württemberg. This work was also supported by the Department of Defense, including grant 10064005/11348001, the French Health Ministry (PHRC), France Parkinson Association, Lille University Hospital (A. Desteé), the Atip/Avenir from the National Institute of Health and Medical Research (INSERM), the ANR in association with the ERA-NET E-rare program, the France Alzheimer Association, and a Career Integration Grant from Marie Curie Actions (E.K.). C.P. received a postdoctoral fellowship from the Cognacq-Jay Foundation. S.C. received postdoctoral fellowships from EMBO and AFM-Telethon. Publisher Copyright: © 2016 The American Society of Human Genetics.

PY - 2016/3/3

Y1 - 2016/3/3

N2 - Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

AB - Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

UR - http://www.scopus.com/inward/record.url?scp=84959881559&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.01.014

DO - 10.1016/j.ajhg.2016.01.014

M3 - Article

C2 - 26942284

AN - SCOPUS:84959881559

SN - 0002-9297

VL - 98

SP - 500

EP - 513

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

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