The GBA p.Trp378Gly Mutation Is a Probable French-Canadian Founder Mutation Causing Gaucher Disease and Synucleinopathies

Clin Genet. 2018 Oct;94(3-4):339-345. doi: 10.1111/cge.13405. Epub 2018 Jul 16.

Abstract

Biallelic GBA mutations cause Gaucher disease (GD), and heterozygous carriers are at risk for synucleinopathies. No founder GBA mutations in French-Canadians are known. GBA was fully sequenced using targeted next generation and Sanger sequencing in French-Canadian Parkinson disease (PD) patients (n = 436), rapid eye movement (REM)-sleep behavior disorder (RBD) patients (n = 189) and controls (n = 891). Haplotype, identity-by-descent (IBD) and principal component analyses (PCA) were performed using single nucleotide polymorphism-chip data. Data on GD patients from Toronto and Montreal were collected from patients' files. A GBA p.Trp378Gly mutation was identified in two RBD and four PD patients (1% of all patients combined), and not in controls. The two RBD patients had converted to DLB within 3 years of their diagnosis. Haplotype, IBD and PCA analysis demonstrated that this mutation is from a single founder. Out of 167 GD patients screened, 15 (9.0%) carried the p.Trp378Gly mutation, all in trans with p.Asn370Ser. Three (20%) of the GD patients with the p.Trp378Gly mutation had developed Parkinsonism, and 11 patients had family history of PD. The p.Trp378Gly mutation is the first French-Canadian founder GBA mutation to be described, which leads to synucleinopathies and to GD type 1 when in compound heterozygosity with p.Asn370Ser.

Keywords: GBA; Gaucher disease; Parkinson disease; REM sleep behavior disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child, Preschool
  • Female
  • Founder Effect*
  • Gaucher Disease / genetics*
  • Glucosylceramidase / genetics*
  • Glycine / genetics*
  • Haplotypes
  • Heterozygote
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation*
  • Polymorphism, Single Nucleotide
  • Principal Component Analysis
  • Quebec
  • Synucleins / genetics*
  • Tryptophan / genetics*
  • Young Adult

Substances

  • Synucleins
  • Tryptophan
  • GBA protein, human
  • Glucosylceramidase
  • Glycine