Identification of Modifier Genes in a Mouse Model of Gaucher Disease

• Published in: Cell reports (Cambridge) Vol. 16; no. 10; pp. 2546 - 2553
• Main Authors: Klein, Andrés D., Ferreira, Natalia-Santos, Ben-Dor, Shifra, Duan, Jingjing, Hardy, John, Cox, Timothy M., Merrill, Alfred H., Futerman, Anthony H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.09.2016; Elsevier
• Subjects: Animals; Base Sequence; Disease Models, Animal; Gaucher Disease - genetics; Genes, Modifier; Genome-Wide Association Study; Injections; Inositol - analogs & derivatives; Inositol - pharmacology; Longevity; Mice, Inbred Strains; Phenotype; Polymorphism, Single Nucleotide - genetics; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.07.085

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. [Display omitted] •Gaucher disease displays considerable phenotypic variability•Genetic variation of mouse strains is used to map Gaucher disease modifier genes•A combination of genotypes predicts the severity of Gaucher disease•An antagonist of the NMDA receptor increases the lifespan of GD mice The variable phenotypes of Gaucher disease (GD) and other lysosomal storage disorders may be due to environmental and genetic factors. Here, Klein et al. induce Gaucher disease in 15 inbred mouse strains. Using a genome-wide association study, they identify 17 putative modifier genes, among them NR2B, the B subunit of the NMDA receptor.