Glucocerebrosidase mutations in primary parkinsonism

Rosanna Asselta, Valeria Rimoldi, Chiara Siri, Roberto Cilia, Ilaria Guella, Silvana Tesei, Giulia Soldà, Gianni Pezzoli, Stefano Duga, Stefano Goldwurm

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Mutations in the lysosomal glucocerebrosidase (GBA) gene increase the risk of Parkinson's Disease (PD). We determined the frequency and relative risk of major GBA mutations in a large series of Italian patients with primary parkinsonism. Methods: We studied 2766 unrelated consecutive patients with clinical diagnosis of primary degenerative parkinsonism (including 2350 PD), and 1111 controls. The entire cohort was screened for mutations in GBA exons 9 and 10, covering approximately 70% of mutations, including the two most frequent defects, p.N370S and p.L444P. Results: Four known mutations were identified in heterozygous state: 3 missense mutations (p.N370S, p.L444P, and p.D443N), and the splicing mutation IVS10+1G>T, which results in the in-frame exon-10 skipping. Molecular characterization of 2 additional rare variants, potentially interfering with splicing, suggested a neutral effect. GBA mutations were more frequent in PD (4.5%, RR=7.2, CI=3.3-15.3) and in Dementia with Lewy Bodies (DLB) (13.8%, RR=21.9, CI=6.8-70.7) than in controls (0.63%). but not in the other forms of parkinsonism such as Progressive Supranuclear Palsy (PSP, 2%), and Corticobasal Degeneration (CBD, 0%). Considering only the PD group, GBA-carriers were younger at onset (52±10 vs. 57±10 years, P

Original languageEnglish
Pages (from-to)1215-1220
Number of pages6
JournalParkinsonism and Related Disorders
Volume20
Issue number11
DOIs
Publication statusPublished - Nov 1 2014

Keywords

  • Association analysis
  • Functional characterization
  • GBA
  • Parkinson's disease
  • Parkinsonism
  • Splicing mutation

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Clinical Neurology
  • Neurology

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