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LRP10 in α-synucleinopathies

2018; Elsevier BV; Volume: 17; Issue: 12 Linguagem: Inglês

10.1016/s1474-4422(18)30399-5

1474-4465

Rita Guerreiro, Tatiana Orme, João Luís Neto, José Brás, Rita Guerreiro, John Hardy, Célia Kun‐Rodrigues, Lee Darwent, Tatiana Orme, João Luís Neto, Susana Carmona, Olaf Ansorge, Laura Parkkinen, Kevin Morgan, Kristelle Brown, Anne Braae, Imelda Barber, Claire Troakes, Safa Al‐Sarraj, Tammaryn Lashley, Janice L. Holton, Yaroslau Compta, Tamás Révész, Andrew Lees, Henrik Zetterberg, Valentina Escott‐Price, Stuart Pickering‐Brown, David Mann, Andrew Singleton, Dena Hernandez, Owen A. Ross, Dennis W. Dickson, Caroline Graff, Tanis J. Ferman, Ronald C. Petersen, Bradley F. Boeve, Michael G. Heckman, John Q. Trojanowski, Vivianna M. Van Deerlin, Nigel J. Cairns, John C. Morris, David A. Stone, John D. Eicher, Lorraine N. Clark, Lawrence S. Honig, Karen Marder, Geidy E. Serrano, Thomas Beach, Douglas Galasko, Eliezer Masliah, Ekaterina Rogaeva, Peter St George‐Hyslop, Jordi Clarimón, Alberto Lleó, Estrella Morenas‐Rodríguez, Pau Pástor, Mónica Díez-Fairén, Miquel Aquilar, Claire E. Shepherd, Glenda M. Halliday, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Isabel Santana, Suzanne Lesage, Elisabet Londos, Afina W. Lemstra, José Brás,

Genetics and Neurodevelopmental Disorders

Marialuisa Quadri and colleagues' recent report1Quadri M Mandemakers W Grochowska MM et al.LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study.Lancet Neurol. 2018; 17: 597-608Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar in The Lancet Neurology on the involvement of LRP10 variants in various α-synucleinopathies is important because it provides a potential novel gene for dementia with Lewy bodies, a disease for which causative genes have been difficult to identify. In an attempt to replicate these results, we mined whole-exome sequencing data from a cohort of 1040 patients with dementia with Lewy bodies and 1422 controls. Patients, who were identified through the International Dementia with Lewy Bodies Genetics Consortium, were included if they met the McKeith criteria2McKeith IG Dickson DW Lowe J et al.Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.Neurology. 2005; 65: 1863-1872Crossref PubMed Scopus (4127) Google Scholar of intermediate or high likelihood for a neuropathological diagnosis of dementia with Lewy bodies; samples without neuropathological information were diagnosed according to established clinical criteria.2McKeith IG Dickson DW Lowe J et al.Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.Neurology. 2005; 65: 1863-1872Crossref PubMed Scopus (4127) Google Scholar Controls were derived from two sources: the 1958 British Birth cohort3Power C Elliott J Cohort profile: 1958 British birth cohort (National Child Development Study).Int J Epidemiol. 2006; 35: 34-41Crossref PubMed Scopus (702) Google Scholar (n=985) and the Healthy Exomes database4Guerreiro R Sassi C Gibbs J et al.A comprehensive assessment of benign genetic variability for neurodegenerative disorders.bioRxiv. 2018; : 270686Google Scholar (n=437). Sequencing of these samples led to the identification of 25 variants, including 14 occurring only in controls and eight occurring exclusively in patients (appendix). Two of the variants identified by Quadri and colleagues in two Dutch individuals were present in our data (Ala212Serfs*17 and Asn517del), in one person each. The individuals with these variants in our study, who were from The Netherlands Brain Bank, also match those in the study by Quadri and colleagues on sex, age at death, and disease duration. Given the extreme rarity of these variants (they are absent from the Genome Aggregation Database5Lek M Karczewski KJ Minikel EV et al.Analysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6538) Google Scholar) and the low probability of these individuals having the same diagnosis as in the previous study, it is very likely that our patients are the same as those described by Quadri and colleagues.1Quadri M Mandemakers W Grochowska MM et al.LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study.Lancet Neurol. 2018; 17: 597-608Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar Additionally, we identified two protein-truncating variants (Gln67* and Arg554* in one case and one control, respectively). No single variant in the gene was associated with dementia with Lewy bodies and the carrier frequency was similar between cases (3%) and controls (3%). To determine whether there is enrichment of variants in LRP10, we performed group-wise association. Variants were grouped into missense, missense and loss-of-function, and loss-of-function only categories, and none of these groups was significantly associated with dementia with Lewy bodies (p=0·4 for missense, p=0·7 for missense and loss-of-function, p=0·3 for loss-of-function). It is difficult to conclusively disprove a pathogenic role for LRP10 variants in dementia with Lewy bodies, particularly given the suggestion of incomplete penetrance and phenocopies within the initially studied families.1Quadri M Mandemakers W Grochowska MM et al.LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study.Lancet Neurol. 2018; 17: 597-608Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar In the cases of SNCA and LRRK2, which Quadri and colleagues used as comparison to LRP10, the original identification of the genes as causative was based on complete segregation in multiple families,6Paisán-Ruíz C Jain S Evans EW et al.Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.Neuron. 2004; 44: 595-600Summary Full Text Full Text PDF PubMed Scopus (1877) Google Scholar, 7Polymeropoulos MH Higgins JJ Golbe LI et al.Mapping of a gene for Parkinson's disease to chromosome 4q21-q23.Science. 1996; 274: 1197-1199Crossref PubMed Scopus (615) Google Scholar which is not the case for LRP10. Our data do not support a role for LRP10 mutations in dementia with Lewy bodies and we await robust independent genetic replication of the original report. We declare no competing interests. Download .pdf (.18 MB) Help with pdf files Supplementary appendix LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing studyOur 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. Full-Text PDF LRP10 in α-synucleinopathiesWe read with interest the recent article by Marialuisa Quadri and colleagues1 The Lancet Neurology, proposing LRP10 as a novel disease-causing gene in autosomal dominant Parkinson's disease and dementia with Lewy bodies. Notably, the authors use the term α-synucleinopathies, which entails not only Lewy body disorders, but also diseases with other patterns of α-synuclein pathology, such as multiple system atrophy. A mixed neuropathological picture, with elements of both Lewy body disease and multiple system atrophy pathology, has been reported in a family in which affected members carried the SNCA mutation GLy51Asp, suggesting that a simple genetic defect could potentially predispose to α-synucleinopathy in a general sense. Full-Text PDF LRP10 in α-synucleinopathiesWe read with interest the Article by Marialuisa Quadri and colleagues1 in The Lancet Neurology, in which they suggested LRP10 mutations as a cause of Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies. As part of the International Parkinson's Disease Genomics Consortium, we analysed LRP10 in exome sequencing data from 2835 individuals with Parksinson's disease and 5343 individuals without known neurological disease (appendix). We also analysed exome sequencing data from 111 individuals with pathologically confirmed dementia with Lewy bodies and another 233 individuals without known neurological disease (appendix). Full-Text PDF LRP10 in α-synucleinopathiesIn The Lancet Neurology, Marialuisa Quadri and colleagues1 reported that rare, potentially pathogenic variants in LRP10 can cause autosomal dominant Parkinson's disease and dementia with Lewy bodies. To assess the causality of LRP10 in our French cohorts, we used data mining in the exomes of 21 families (61 individuals) with autosomal dominant Parkinson's disease, four families (nine individuals) with dementia with Lewy bodies, and 66 individuals with sporadic Parkinson's disease (appendix). Mutations in parkinsonism-associated genes2 were excluded by exome sequencing and multiplex ligation-dependent probe amplification. Full-Text PDF LRP10 in α-synucleinopathies – Authors' replyWe thank Kia and colleagues, Guerreiro and colleagues, Pihlstrøm and colleagues, Tesson and colleagues, and Shi and colleagues for their interest in our work.1 Full-Text PDF LRP10 in α-synucleinopathiesThe Lancet Neurology, Marialuisa Quadri and colleagues1 recently identified variants in LRP10 in families with autosomal dominant Parkinson's disease and dementia with Lewy bodies. Nine rare LRP10 variants were identified in 11 probands with Parkinson's disease or dementia with Lewy bodies from Europe, Brazil, and Taiwan. Ten of these probands had a positive family history of Parkinson's disease or dementia with Lewy bodies, suggesting that rare LRP10 variants might contribute to inherited forms of these diseases. Full-Text PDF