title: Glucocerebrosidase mutations in primary parkinsonism.
abstract: BACKGROUND
  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 < 0.0001) and were more likely to have a positive family history of PD (34% vs. 20%, P < 0.001).
  
  
  CONCLUSIONS
  GBA dysfunction is relevant for synucleinopathies, such as PD and DLB, except for MSA, in which pathology involves oligodendrocytes, and the tauopathies PSP and CBD. The risk of developing DLB is three-fold higher than PD, suggesting a more aggressive phenotype.
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Rimoldi
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Siri
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cilia
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Guella
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Tesei
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Soldà
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy. Electronic address: stefano.duga@unimi.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
authors.affiliation: Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy. Electronic address: goldwurm@parkinson.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011712:Pyramidal Tracts / Q000473:pathology; D012189:Retrospective Studies; D013494:Supranuclear Palsy, Progressive / Q000235:genetics
chemical_list: D005962:Glucosylceramidase
keywords: Association analysis; Functional characterization; GBA; Parkinson's disease; Parkinsonism; Splicing mutation