Objective: To examine and characterize founder GBA mutations in the French-Canadian (FC) population

Background: GBA mutations are the most common genetic risk factors for Parkinson’s disease (PD), very common in dementia with Lewy bodies (DLB), and biallelic GBA mutations may lead to Gaucher disease (GD). Thus far, founder FC GBA mutations have not been identified.

Methods: Full sequencing of the coding regions and exon-intron boundaries of GBA was performed in a total of 1516 individuals of reported FC ancestry: patients with REM sleep behavior disorder (RBD; n=189), PD patients (n=436), and controls (n=891). Sequencing was performed by using a combination of targeted next generation sequencing with molecular inversion probes, and Sanger sequencing. Clinical data and GBA status were collected from 111 GD patients. To examine ancestry, haplotype and principal component analyses were performed, and the crystal structure of GBA was analyzed using PyMOL v 1.5.

Results: A GBA p.W378G mutation was identified in 2 RBD and 4 PD patients, thus in about 1% of FC patients with RBD/PD. This mutation was not identified in our controls nor in public whole exome/genome sequencing databases (Exac, gnomAD). Interestingly, the two RBD patients developed typical DLB, and had other motor and non-motor symptoms. Among PD patients, data on age at onset were available for 2 carriers of the p.W378G mutation (50 and 52 years). Of the 111 GD patients analyzed, 7 patients from 5 families carried the p.W378G mutation in trans with p.N370S. All 7 GD patients are of French-Canadian origin, and two of them have parkinsonism. Family history of PD was reported in 3 families, and in an additional family, history of dementia was reported. No homozygous carriers of p.W378G were identified. Haplotype analysis demonstrated that the p.W378G mutation is a founder FC mutation. This mutation is located between two important sites for the enzymatic activity of GBA; the active site, and the binding site of saposin C, hence it potentially affects both.

Conclusions: Our results suggest that the GBA p.W378G mutation is a founder FC mutation which, which leads to synucleinopathies and to GD when in compound heterozygosity with p.N370S. The p.W378G mutation may be a severe mutation and homozygosity may be lethal, as suggested by the lack of homozygous carriers of this mutation, however, further studies are needed to examine this hypothesis.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-founder-french-canadian-gba-mutation-p-w378g-as-a-cause-for-synucleinopathies-and-gaucher-disease/