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

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. (c) 2012 Movement Disorder Society