LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study

Autor: Marialuisa Quadri, Wim Mandemakers, Martyna M Grochowska, Roy Masius, Hanneke Geut, Edito Fabrizio, Guido J Breedveld, Demy Kuipers, Michelle Minneboo, Leonie J M Vergouw, Ana Carreras Mascaro, Ekaterina Yonova-Doing, Erik Simons, Tianna Zhao, Alessio B Di Fonzo, Hsiu-Chen Chang, Piero Parchi, Marta Melis, Leonor Correia Guedes, Chiara Criscuolo, Astrid Thomas, Rutger W W Brouwer, Daphne Heijsman, Angela M T Ingrassia, Giovanna Calandra Buonaura, Janneke P Rood, Sabina Capellari, Annemieke J Rozemuller, Marianna Sarchioto, Hsin Fen Chien, Nicola Vanacore, Simone Olgiati, Yah-Huei Wu-Chou, Tu-Hsueh Yeh, Agnita J W Boon, Susanne E Hoogers, Mehrnaz Ghazvini, Arne S IJpma, Wilfred F J van IJcken, Marco Onofrj, Paolo Barone, David J Nicholl, Andreas Puschmann, Michele De Mari, Anneke J Kievit, Egberto Barbosa, Giuseppe De Michele, Danielle Majoor-Krakauer, John C van Swieten, Frank J de Jong, Joaquim J Ferreira, Giovanni Cossu, Chin-Song Lu, Giuseppe Meco, Pietro Cortelli, Wilma D J van de Berg, Vincenzo Bonifati, Anneke J.A. Kievit, Agnita J.W. Boon, Janneke P.A Rood, Leonie J.M. Vergouw, Frank J. de Jong, John C. van Swieten, Francesco U.S. Mattace-Raso, Klaus L. Leenders, Joaquim J. Ferreira, Emil Ygland, Christer Nilsson, Hsin F. Chien, Laura Bannach Jardim, Carlos R.M. Rieder, Leonardo Lopiano, Cristina Tassorelli, Claudio Pacchetti, Giulio Riboldazzi, Giorgio Bono, Cristoforo Comi, Alessandro Padovani, Barbara Borroni, Francesco Raudino, Emiliana Fincati, Michele Tinazzi, Alberto Bonizzato, Carlo Ferracci, Alessio Dalla Libera, Giovanni Abbruzzese, Roberto Marconi, Marco Guidi, Giovanni Fabbrini, Alfredo Berardelli, Fabrizio Stocchi, Laura Vacca, Marina Picillo, Claudia Dell'Aquila, Gianni Iliceto, Vincenzo Toni, Giorgio Trianni, Monica Gagliardi, Grazia Annesi, Aldo Quattrone, Valeria Saddi, Gianni Cossu, Maurizio Melis
Přispěvatelé: Quadri, Marialuisa, Mandemakers, Wim, Grochowska, Martyna M, Masius, Roy, Geut, Hanneke, Fabrizio, Edito, Breedveld, Guido J, Kuipers, Demy, Minneboo, Michelle, Vergouw, Leonie J M, Carreras Mascaro, Ana, Yonova-Doing, Ekaterina, Simons, Erik, Zhao, Tianna, Di Fonzo, Alessio B, Chang, Hsiu-Chen, Parchi, Piero, Melis, Marta, Correia Guedes, Leonor, Criscuolo, Chiara, Thomas, Astrid, Brouwer, Rutger W W, Heijsman, Daphne, Ingrassia, Angela M T, Calandra Buonaura, Giovanna, Rood, Janneke P, Capellari, Sabina, Rozemuller, Annemieke J, Sarchioto, Marianna, Fen Chien, Hsin, Vanacore, Nicola, Olgiati, Simone, Wu-Chou, Yah-Huei, Yeh, Tu-Hsueh, Boon, Agnita J W, Hoogers, Susanne E, Ghazvini, Mehrnaz, IJpma, Arne S, van IJcken, Wilfred F J, Onofrj, Marco, Barone, Paolo, Nicholl, David J, Puschmann, Andrea, De Mari, Michele, Kievit, Anneke J, Barbosa, Egberto, De Michele, Giuseppe, Majoor-Krakauer, Danielle, van Swieten, John C, de Jong, Frank J, Ferreira, Joaquim J, Cossu, Giovanni, Lu, Chin-Song, Meco, Giuseppe, Cortelli, Pietro, van de Berg, Wilma D J, Bonifati, Vincenzo, Netherlands Institute for Neuroscience (NIN), Amsterdam Neuroscience - Neurodegeneration, Neurology, Anatomy and neurosciences, Pathology, Clinical Genetics, Erasmus MC other, Cell biology, Developmental Biology, Ijpma, Arne S
Rok vydání: 2018
Předmět:
Zdroj: The Lancet Neurology, 17, 597-608. Lancet Publishing Group
The Lancet Neurology, 17(7), 597-608. Lancet Publishing Group
Lancet Neurology, 17(7), 597-608. Lancet Publishing Group
International Parkinsonism Genetics Network 2018, ' LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies : a genome-wide linkage and sequencing study ', The Lancet Neurology, vol. 17, no. 7, pp. 597-608 . https://doi.org/10.1016/S1474-4422(18)30179-0
ISSN: 1474-4465
1474-4422
DOI: 10.1016/S1474-4422(18)30179-0
Popis: Summary Background Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. Methods Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells. Findings Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59·8 years [SD 8·7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent—albeit limited—evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G→A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immunocytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism. Interpretation Our findings implicate LRP10 gene defects in the development of inherited forms of α-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets. Funding Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw—Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Lakarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands–Ligue Europeene Contre la Maladie d'Alzheimer (LECMA).
Databáze: OpenAIRE
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