Arianna Manini1, Letizia Straniero2, Edoardo Monfrini3, Marco Percetti4, Maria Vizziello3, Giulia Franco5, Valeria Rimoldi2, Anna Zecchinelli6, Gianni Pezzoli6, Stefania Corti5, Giacomo Pietro Comi5, Stefano Duga7, Alessio Di Fonzo8. 1. Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; "Luigi Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy. 2. Department of Biomedical Sciences, Humanitas University, Milan, Italy. 3. Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. 4. Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Neurology Unit, San Gerardo Hospital, ASST Monza, Monza, Italy. 5. Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy. 6. Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy; Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy. 7. Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Clinical and Research Center, IRCCS, Milan, Italy. 8. Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy. Electronic address: alessio.difonzo@policlinico.mi.it.
Abstract
INTRODUCTION: Parkinson's disease (PD) belongs to a family of neurodegenerative diseases characterized by alpha-synuclein accumulation in neurons, whose etiopathogenesis remains largely uncovered. Recently, LRP10 has been associated with PD, Parkinson's disease Dementia (PDD) and Dementia with Lewy Bodies (DLB) by linkage analysis and positional cloning in an Italian family with late-onset PD. After the first characterization of a LRP10 pathogenic variant, other eight mutations have been detected in an international series of 660 probands with either a clinical or pathological diagnosis of PD, PDD or DLB. However, the results of following replication studies were inconclusive and the pathogenic role of LRP10 is still debated. The aim of this study is to sequence the LRP10 gene in an Italian cohort of clinically-diagnosed PD patients and to compare the frequency of the identified variants with the ones found in a large cohort of Italian exomes. METHODS: A cohort of 664 PD patients was analyzed by targeted Next Generation Sequencing approach. Identified LRP10 variants were subsequently confirmed by Sanger sequencing and searched for in an in-house database including 3596 Italian exomes. RESULTS: We identified three PD patients carrying a rare heterozygous, potentially pathogenic variant (p.R296C, p.R549Q, p.R661C). None of them was detected in 3596 Italian exomes. Two of them (p.R296C and p.R661C) have been previously reported in one sporadic PD and one definite Progressive supranuclear palsy patients respectively. All three carriers had late-onset PD responsive to levodopa, characterized by both motor and non-motor features, but no cognitive impairment. CONCLUSION: We report three rare possibly-pathogenic LRP10 variants in PD patients from Italy. Further investigations are required to definitively establish their role in alpha-synucleinopathies.
INTRODUCTION: Parkinson's disease (PD) belongs to a family of neurodegenerative diseases characterized by alpha-synuclein accumulation in neurons, whose etiopathogenesis remains largely uncovered. Recently, LRP10 has been associated with PD, Parkinson's disease Dementia (PDD) and Dementia with Lewy Bodies (DLB) by linkage analysis and positional cloning in an Italian family with late-onset PD. After the first characterization of a LRP10 pathogenic variant, other eight mutations have been detected in an international series of 660 probands with either a clinical or pathological diagnosis of PD, PDD or DLB. However, the results of following replication studies were inconclusive and the pathogenic role of LRP10 is still debated. The aim of this study is to sequence the LRP10 gene in an Italian cohort of clinically-diagnosed PD patients and to compare the frequency of the identified variants with the ones found in a large cohort of Italian exomes. METHODS: A cohort of 664 PD patients was analyzed by targeted Next Generation Sequencing approach. Identified LRP10 variants were subsequently confirmed by Sanger sequencing and searched for in an in-house database including 3596 Italian exomes. RESULTS: We identified three PD patients carrying a rare heterozygous, potentially pathogenic variant (p.R296C, p.R549Q, p.R661C). None of them was detected in 3596 Italian exomes. Two of them (p.R296C and p.R661C) have been previously reported in one sporadic PD and one definite Progressive supranuclear palsy patients respectively. All three carriers had late-onset PD responsive to levodopa, characterized by both motor and non-motor features, but no cognitive impairment. CONCLUSION: We report three rare possibly-pathogenic LRP10 variants in PD patients from Italy. Further investigations are required to definitively establish their role in alpha-synucleinopathies.