title: Mouse model of glycogen storage disease type III.
abstract: Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of the glycogen debranching enzyme (GDE), which is encoded by the Agl gene. GDE deficiency leads to the pathogenic accumulation of phosphorylase limit dextrin (PLD), an abnormal glycogen, in the liver, heart, and skeletal muscle. To further investigate the pathological mechanisms behind this disease and develop novel therapies to treat this disease, we generated a GDE-deficient mouse model by removing exons after exon 5 in the Agl gene. GDE reduction was confirmed by western blot and enzymatic activity assay. Histology revealed massive glycogen accumulation in the liver, muscle, and heart of the homozygous affected mice. Interestingly, we did not find any differences in the general appearance, growth rate, and life span between the wild-type, heterozygous, and homozygous affected mice with ad libitum feeding, except reduced motor activity after 50 weeks of age, and muscle weakness in both the forelimb and hind legs of homozygous affected mice by using the grip strength test at 62 weeks of age. However, repeated fasting resulted in decreased survival of the knockout mice. Hepatomegaly and progressive liver fibrosis were also found in the homozygous affected mice. Blood chemistry revealed that alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities were significantly higher in the homozygous affected mice than in both wild-type and heterozygous mice and the activity of these enzymes further increased with fasting. Creatine phosphokinase (CPK) activity was normal in young and adult homozygous affected mice. However, the activity was significantly elevated after fasting. Hypoglycemia appeared only at a young age (3 weeks) and hyperlipidemia was not observed in our model. In conclusion, with the exception of normal lipidemia, these mice recapitulate human GSD IIIa; moreover, we found that repeated fasting was detrimental to these mice. This mouse model will be useful for future investigation regarding the pathophysiology and treatment strategy of human GSD III.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, 155, Sec.2, Linong Street, Taipei 112, Taiwan.
authors.forename: Kai-Ming
authors.initials: KM
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Department of Pediatrics, Duke University Medical Center, Box 3528, Durham, NC 27710, USA. Electronic address: chen0010@ibms.sinica.edu.tw.
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005215:Fasting / Q000097:blood; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006004:Glycogen Debranching Enzyme System / Q000172:deficiency / Q000235:genetics; D006010:Glycogen Storage Disease Type III / Q000097:blood / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D015151:Immunoblotting; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053580:Muscle Strength; D009928:Organ Specificity
chemical_list: D006004:Glycogen Debranching Enzyme System; D006003:Glycogen
keywords: GDE; GSD III; Glycogen debranching enzyme; Glycogen storage disease type III; Mouse model