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Identification of Modifier Genes in a Mouse Model of Gaucher Disease.

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Klein, Andrés D 
Ferreira, Natalia-Santos 
Ben-Dor, Shifra 
Duan, Jingjing 
Hardy, John 


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.



Animals, Base Sequence, Disease Models, Animal, Gaucher Disease, Genes, Modifier, Genome-Wide Association Study, Injections, Inositol, Longevity, Mice, Inbred Strains, Phenotype, Polymorphism, Single Nucleotide, Receptors, N-Methyl-D-Aspartate

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Elsevier BV
Medical Research Council (MR/K015338/1)
Medical Research Council (MR/K025570/1)
Children’s Gaucher Research Fund, Pfizer, Minerva Foundation, National Institutes of Health (Grant ID: GM076217), Medical Research Council (Grant ID: MR/K015338/1), Cambridge Biomedical Research Centre of National Institute for Health Research, UK Gaucher Association, Rosetrees Trust, Weizmann Institute of Science