Identification of Modifier Genes in a Mouse Model of Gaucher Disease

Abstract

Diseases caused by single-gene mutations can display substantial phenotypic variability, which may be due to genetic, environmental, or epigenetic modifiers. Here, we induce Gaucher disease (GD), a rare inherited metabolic disorder, by injecting 15 inbred mouse strains with a low dose of a chemical inhibitor of acid β-glucosidase, the enzyme defective in GD. Different mouse strains exhibit widely different lifespans, which is unrelated to levels of acid β-glucosidase's substrate accumulation. Genome-wide association reveals a number of candidate risk loci, including a marker within Grin2b, which in combination with another marker allows us to predict the lifespan of additional mouse strains. An antagonist of the NMDA receptor (encoded by Grin2b) significantly increases the lifespan of GD mice that would otherwise have lived for a short time. Our data identify putative modifier genes that may be involved in determining GD severity, which might help elucidate phenotypic variability between patients with similar GD mutations.

Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

“…CBE has been used to induce a chemical model of Gaucher disease in neonatal mice 26 . However, the toxicity of CBE is very widely variable depending on mouse strain 62 . Even though lysosomal GCase is inhibited by 90–95% at a daily dose of 25 mg/kg/day starting at neonatal age, there is no correlation between lifespan and residual enzyme activity.…”

Gaucher disease: Progress and ongoing challenges

“…Furthermore, patients sharing the same mutations, even siblings or twins, could have different phenotypes, complications and responses to therapy. Mutation L444P at times was encountered as an isolated point mutation, and in other instances was part of a recombinant allele resulting from recombination with the nearby and homologous pseudogene sequence [30, 31]. The N370S mutation is generally considered to be exclusively associated with non-neuronopathic forms of GD, and homozygosity for the mutation is often predictive of milder disease features and is frequent in asymptomatic individuals [32].…”

“…The N370S mutation is generally considered to be exclusively associated with non-neuronopathic forms of GD, and homozygosity for the mutation is often predictive of milder disease features and is frequent in asymptomatic individuals [32]. However, other efforts to correlate genotype with specific phenotype features have been incomplete, and suggest the existence of additional genetic modifiers [30, 33]. Some mutant GBA1 alleles are common, while others are private, and they include point mutations, insertions, deletions, splice-site alterations and mutations that result from recombination with the nearby pseudogene.…”

“…The Futerman lab improved on this model though optimizing dose and timing of CBE administration to generate longer-lived models replicating neuronopathic Gaucher disease [30]. This system was recently employed to describe impressive variability of Gaucher disease phenotypes in different strains of mice and a genome-wide association study has led to a list of compelling candidate modifier genes.…”

Perspective: Finding common ground

“…Use of a chemical inhibitor of glucocerebrosidase could help researchers to develop longer-living models of Gaucher's disease. A recent study 12 that used this approach has led to the discovery of a number of genes that might modify the severity of both Gaucher's and Parkinson's diseases.…”