TY - JOUR
T1 - Identification of Modifier Genes in a Mouse Model of Gaucher Disease
AU - Klein, Andres D
AU - Ferreira, Natalia-Santos
AU - Ben-Dor, Shifra
AU - Duan, Jingjing
AU - Hardy, John
AU - Cox, Timothy M
AU - Merrill, Alfred H Jr
AU - Futerman, Anthony H.
N1 - This study was partially supported by the Children’s Gaucher Research Fund, an Investigator-Initiated Research grant from Pfizer, the Minerva Foundation, and the NIH grant GM076217. T.M.C. was supported by an MRC grant (MR/K015338/1) and the Cambridge Biomedical Research Centre of NIHR. We thank R. Rotkopf for help with R package and E. Feldmesser and I. Orr for help with the microarray analysis (Bioinformatics Unit, Weizmann Institute of Science). A.D.K. was supported by a fellowship from the UK Gaucher Association and by the Rosetrees Trust. A.H.F. is the Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science. A.D.K. designed and performed most of the experiments and helped write the manuscript. N.-S.F. performed additional crucial experiments and J.D. also helped with some experiments. S.B.-D., T.M.C., J.H., and A.H.M. helped with experimental design and planning. A.H.F. participated in experimental design, supervised, and funded the project, and wrote the manuscript.
PY - 2016/9/6
Y1 - 2016/9/6
N2 - 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 beta-glucosidase, the enzyme defective in GD. Different mouse strains exhibit widely different lifespans, which is unrelated to levels of acid beta-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.
AB - 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 beta-glucosidase, the enzyme defective in GD. Different mouse strains exhibit widely different lifespans, which is unrelated to levels of acid beta-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.
UR - http://www.scopus.com/inward/record.url?scp=85006401138&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.07.085
DO - 10.1016/j.celrep.2016.07.085
M3 - مقالة
SN - 2211-1247
VL - 16
SP - 2546
EP - 2553
JO - Cell Reports
JF - Cell Reports
IS - 10
ER -