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. 2018 Jul;17(7):597-608.
doi: 10.1016/S1474-4422(18)30179-0. Epub 2018 Jun 7.

LRP10 Genetic Variants in Familial Parkinson's Disease and Dementia With Lewy Bodies: A Genome-Wide Linkage and Sequencing Study

Collaborators, Affiliations

LRP10 Genetic Variants in Familial Parkinson's Disease and Dementia With Lewy Bodies: A Genome-Wide Linkage and Sequencing Study

Marialuisa Quadri et al. Lancet Neurol. .

Erratum in

Abstract

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 Läkarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands-Ligue Européene Contre la Maladie d'Alzheimer (LECMA).

Comment in

  • A novel link between trafficking and Lewy body disorders.
    Ross OA, Bu G. Ross OA, et al. Lancet Neurol. 2018 Jul;17(7):571-573. doi: 10.1016/S1474-4422(18)30214-X. Epub 2018 Jun 7. Lancet Neurol. 2018. PMID: 29887160 No abstract available.
  • LRP10 in α-synucleinopathies.
    Kia DA, Sabir MS, Ahmed S, Trinh J, Bandres-Ciga S; International Parkinson's Disease Genomics Consortium. Kia DA, et al. Lancet Neurol. 2018 Dec;17(12):1032. doi: 10.1016/S1474-4422(18)30401-0. Epub 2018 Nov 13. Lancet Neurol. 2018. PMID: 30507383 No abstract available.
  • LRP10 in α-synucleinopathies.
    Guerreiro R, Orme T, Neto JL, Bras J; International DLB Genetics Consortium. Guerreiro R, et al. Lancet Neurol. 2018 Dec;17(12):1032-1033. doi: 10.1016/S1474-4422(18)30399-5. Epub 2018 Nov 13. Lancet Neurol. 2018. PMID: 30507384 No abstract available.
  • LRP10 in α-synucleinopathies.
    Pihlstrøm L, Schottlaender L, Chelban V, Houlden H; MSA Exome Consortium. Pihlstrøm L, et al. Lancet Neurol. 2018 Dec;17(12):1033-1034. doi: 10.1016/S1474-4422(18)30407-1. Epub 2018 Nov 13. Lancet Neurol. 2018. PMID: 30507385 No abstract available.
  • LRP10 in α-synucleinopathies.
    Tesson C, Brefel-Courbon C, Corvol JC, Lesage S, Brice A; French Parkinson's Disease Genetics Study Group. Tesson C, et al. Lancet Neurol. 2018 Dec;17(12):1034. doi: 10.1016/S1474-4422(18)30400-9. Epub 2018 Nov 13. Lancet Neurol. 2018. PMID: 30507386 No abstract available.
  • LRP10 in α-synucleinopathies.
    Shi CH, Luo HY, Fan Y, Li YS, Xu YM. Shi CH, et al. Lancet Neurol. 2018 Dec;17(12):1034-1035. doi: 10.1016/S1474-4422(18)30402-2. Epub 2018 Nov 13. Lancet Neurol. 2018. PMID: 30507387 No abstract available.
  • LRP10: A novel disease gene bridging Parkinson's disease and dementia with Lewy body.
    Morgante F, Valente EM. Morgante F, et al. Mov Disord. 2019 Jan;34(1):47. doi: 10.1002/mds.27593. Epub 2018 Dec 30. Mov Disord. 2019. PMID: 30597596 No abstract available.

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