title: The glucocerobrosidase E326K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease.
abstract: BACKGROUND
  Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher's disease (GD), are the strongest known risk factor for Parkinson's disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD.
  
  
  METHODS
  One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing.
  
  
  RESULTS
  We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD.
  
  
  CONCLUSIONS
  Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease.
authors.affiliation: Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Raquel
authors.initials: R
authors.lastname: Duran
authors.affiliation: Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Department of Neurology and Laboratory of Neuroscience, "Dino Ferrari" Center, Universitá degli Studi di Milano, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Niccolo E
authors.initials: NE
authors.lastname: Mencacci
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK.
authors.forename: Aikaterini V
authors.initials: AV
authors.lastname: Angeli
authors.affiliation: Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Shoai
authors.affiliation: Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Deas
authors.affiliation: Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Lysosomal Storage Disorders Unit, Department of Haematology, UCL Medical School, Royal Free Hospital, London, UK.
authors.forename: Atul
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Lysosomal Storage Disorders Unit, Department of Haematology, UCL Medical School, Royal Free Hospital, London, UK.
authors.forename: Derralynn
authors.initials: D
authors.lastname: Hughes
authors.affiliation: Lysosomal Diseases Unit, Addenbrookes Hospital, and Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Cox
authors.affiliation: Lysosomal Diseases Unit, Addenbrookes Hospital, and Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Deegan
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, UCL Medical School, Royal Free Hospital, London, UK.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Schapira
authors.affiliation: Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Limousin
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jarman
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.affiliation: Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.affiliation: Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Foltynie
mesh_terms: D000328:Adult; D017668:Age of Onset; D004247:DNA / Q000235:genetics; D030541:Databases, Genetic; D005091:Exons / Q000235:genetics; D005260:Female; D005776:Gaucher Disease / Q000453:epidemiology / Q000235:genetics; D005787:Gene Frequency; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D007962:Leukocytes / Q000201:enzymology; D020961:Lewy Body Disease / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology; D044465:White People; D055815:Young Adult
chemical_list: D004247:DNA; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005962:Glucosylceramidase