title: 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.
authors: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Andrés D
authors: AD
authors: Klein
authors: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Natalia-Santos
authors: NS
authors: Ferreira
authors: Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Shifra
authors: S
authors: Ben-Dor
authors: School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30318, USA.
authors: Jingjing
authors: J
authors: Duan
authors: University College London, Institute of Neurology, London WC1N 3BG, UK.
authors: John
authors: J
authors: Hardy
authors: Department of Medicine, University of Cambridge, Cambridge CB2 1TN, UK.
authors: Timothy M
authors: TM
authors: Cox
authors: School of Biology and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30318, USA.
authors: Alfred H
authors: AH
authors: Merrill
authors: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: tony.futerman@weizmann.ac.il.
authors: Anthony H
authors: AH
authors: Futerman
mesh_terms: D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000235:genetics*; D060045:Genes, Modifier; D055106:Genome-Wide Association Study; D007267:Injections; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D008136:Longevity; D008815:Mice, Inbred Strains; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D007294:Inositol; C011423:conduritol epoxide