The glucocerobrosidase E326K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease

Mov Disord. 2013 Feb;28(2):232-236. doi: 10.1002/mds.25248. Epub 2012 Dec 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • DNA / genetics
  • Databases, Genetic
  • European Continental Ancestry Group
  • Exons / genetics
  • Female
  • Gaucher Disease / epidemiology
  • Gaucher Disease / genetics
  • Gene Frequency
  • Glucosylceramidase / genetics*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Leukocytes / enzymology
  • Lewy Body Disease / genetics
  • Lewy Body Disease / pathology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics
  • Open Reading Frames / genetics
  • Parkinson Disease / epidemiology
  • Parkinson Disease / genetics*
  • Protein-Serine-Threonine Kinases / genetics
  • Sequence Analysis, DNA
  • Ubiquitin-Protein Ligases / genetics
  • United Kingdom / epidemiology
  • Young Adult


  • DNA
  • Ubiquitin-Protein Ligases
  • parkin protein
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases
  • Glucosylceramidase