Glucocerebrosidase mutations are not a common risk factor for Parkinson disease in North Africa

Abstract

Mutations in the glucocerebrosidase gene (GBA) have recently been associated with an increased risk of Parkinson disease (PD). GBA mutations have been observed to be particularly prevalent in the Ashkenazi Jewish population. Interestingly, this population also has a high incidence of the Lrrk2 p.G2019S mutation which is similar in North African Arab-Berber populations. Herein, our sequencing of the GBA gene, in 33 North African Arab-Berber familial parkinsonism probands, identified two novel mutations in three individuals (p.K-26R and p.K186R). Segregation analysis of these two variants did not support a pathogenic role. Genotyping of p.K-26R, p.K186R and the common p.N370S in an ethnically matched series consisting of 395 patients with PD and 372 control subjects did not show a statistically significant association (P>0.05). The p.N370S mutation was only identified in 1 sporadic patient with PD and 3 control subjects indicating that the frequency of this mutation in the North African Arab-Berber population is much lower than that observed in Ashkenazi Jews, and therefore arose in the latter after expansion of the Lrrk2 p.G2019S variant in North Africa.

Figure 1

Global distribution of GBA p.N370S mutant. The frequency of p.N370S in patients with PD followed by the frequency in control subjects is given for each population [1, 2, 5-7, 9, 17-22, 24, 26, 27, 30]. *Ashkenazi Jewish population.

Figure 2

Schematic of GBA (NM_000157). Position of the novel mutations identified and p.N370S are given. Double nomenclature with and without the absence of the signal peptide is given for all mutations. Exons encoding the signal peptide are shaded.