Abstract
Background: Gaucher disease (GD), caused by a deficiency of the glucocerebrosidase (GC) enzyme, is characterized by the accumulation of glucosylceramide (GlcCer) within lysosomes, resulting in cellular dysfunction and damage. GlcCer is catalyzed by the glucosylceramide synthase (GCS), also known as UDP-glucose ceramide glucosyltransferase, (UGCG), EC 2.4.1.80, first enzyme in glycosphingolipids biosynthesis. Mutations in the glucocerebrosidase (GBA) gene are required to cause GD, but other factors play an important role.
Aims: GCS gene is a logical candidate to hypothesize that its variability could be involved in clinical severity.
Patients and methods: We have analyzed GCS variants (g.(−295)C>T, g.(−222)ins10, g.148A>G, g.166A>T, g.25510C>G, g.29312A>G and g.34991A>G) in a group of 80 [N370S]+[L444P] heterozygous and 23 N370S homozygous patients.
Results: were related with severity score index (SSI). g.(−295)C>T and g.166A>T SNPs were in complete linkage disequilibrium. In the N370S homozygous, carriers of g.(−222)ins10 have higher SSI than non carriers (6.6 vs 2.4, p<0.004). Patient carriers of the A-allele for SNP g.148A>G had higher SSI than the G-allele carriers (6.7 vs 1.5, p<0.001, for [N370S]+[L444P] heterozygous and 4.3 vs 1.7, p<0.001, for [N370S] homozygous). “In silico” studies and electrophoretic mobility shift assay (EMSA) indicate that 10bp insertion at the promoter region generates a new ETF binding site and the g.148a>g variant at intron 1 changes the affinity for the transcription factor AP-2. GlcCer were elevated in patient carriers of one mutated allele of these two variants.
Conclusion: our results suggest that the genetic GCS variants could influence in the development and progression of GD severity.
A New Brain‐Penetrant Glucosylceramide Synthase Inhibitor as Potential Therapeutics for Gaucher Disease
