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.

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

“…The GBA p.E365K [p.E326K] mutation is considered a mild mutation as it has been demonstrated to reduce rather than abolish glucocerebrosidase enzyme activity (Alcalay, et al, 2015; Malini, et al, 2014). As such, homozygosity for this mutation is not sufficient to cause Gaucher disease; however, an increased frequency of heterozygous carriers has been demonstrated in cohorts of Parkinson disease supporting the notion that this mutation is pathogenic (Duran, et al, 2013; Nichols, et al, 2009). The GBA mutation p.R87Q [p.R48Q] has been previously described in a patient with Gaucher disease, but a role in parkinsonism for this particular rare mutation has not yet been reported (Rozenberg, et al, 2006).…”

Blood lysosphingolipids accumulation in patients with parkinson's disease with glucocerebrosidase 1 mutations

“…Interestingly, more “severe” mutations (eg, 84GG or L444P) are associated with a higher risk for PD and with earlier PD onset when compared with “milder” mutations (eg, N370S) . GBA polymorphic variants (E326K, T369M) do not lead to GD but predispose to PD in most studies …”

Genetic risk factors in Parkinson’s disease

“…A recent study has suggested that the GBA p.E326K variant could be the major driver of one of the GBA GWAS signals (Berge-Seidl et al 2017). Notably, this variant is not sufficient to cause Gaucher’s disease (Duran et al 2013) and it appears to have a lower odds ratio in PD compared to other Gaucher’s disease-linked mutations. Although this mutation on its own decreases glucocerebrosidase activity, residual activity is still better than other Gaucher’s disease mutations such as p.N370S and p.L444P (McNeill et al 2014).…”