title: A detailed characterization of the adult mouse model of glycogen storage disease Ia.
abstract: Glycogen storage disease type Ia (GSDIa) is caused by a genetic defect in the hepatic enzyme glucose-6-phosphatase (G6Pase-alpha), which manifests as life-threatening hypoglycemia with related metabolic complications. A G6Pase-alpha knockout (KO) mouse model was generated to study potential therapies for correcting this disorder. Since then, gene therapy studies have produced promising results, showing long-term improvement in liver histology and glycogen metabolism. Under existing protocols, however, untreated KO pups seldom survived weaning. Here, we present a thorough characterization of the G6Pase-alpha KO mouse, as well as the husbandry protocol for rearing this strain to adulthood. These mice were raised with only palliative care, and characterized from birth through 6 months of age. Once KO mice have survived the very frail weaning period, their size, agility, serum lipids and glycemic control improve dramatically, reaching levels approaching their wild-type littermates. In addition, our data reveal that adult mice lacking G6Pase-alpha are able to mate and produce viable offspring. However, liver histology and glycogen accumulation do not improve with age. Overall, the reliable production of mature KO mice could provide a critical tool for advancing the GSDIa field, as the availability of a robust enzyme-deficient adult offers a new spectrum of treatment avenues that would not be tolerated by the frail pups. Most importantly, our detailed characterization of the adult KO mouse provides a crucial baseline for accurately gauging the efficacy of experimental therapies in this important model.
authors: Department of Pathology, Immunology and Laboratory Medicine and The Program for Stem Cell Biology and Regenerative Medicine, University of Florida College of Medicine, Gainesville, FL 32610-0275, USA.
authors: Susan V
authors: SV
authors: Salganik
authors: David A
authors: DA
authors: Weinstein
authors: Thomas D
authors: TD
authors: Shupe
authors: Max
authors: M
authors: Salganik
authors: Dana G
authors: DG
authors: Pintilie
authors: Bryon E
authors: BE
authors: Petersen
mesh_terms: D000822:Animal Husbandry / Q000379:methods; D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism*; D005953:Glycogen Storage Disease Type I / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology*; D008112:Liver Glycogen / Q000032:analysis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D012098:Reproduction / Q000502:physiology; D014886:Weaning
chemical_list: D008112:Liver Glycogen; D005952:Glucose-6-Phosphatase; D020558:GTP Phosphohydrolases