OMIA 001577-9615 : Glycogen storage disease IIIa in Canis lupus familiaris
The mode of inheritance is autosomal recessive. The causative mutation is an adenosine deletion causing premature termination of AGL translation. A test is available to detect the mutation. Parents and siblings of affected dogs should be tested. Breeding of affected animals is not recommended. If a carrier must be bred, it is advised to breed that dog only to a dog that has tested as homozygous normal.
Edited by John C. Fyfe, D.V.M., Ph.D.Mapping: CFA6 Molecular basis: The causative mutation is an adenosine deletion causing premature termination of AGL translation (Gregory et al., 2007). There is an analogous human condition (OMIM# 232400). Clinical features: Affected dogs show increases in ALT, ALP, and CK within the first year of life. By 14 months of age, lethargy, exercise intolerance, and collapse after exercise may become apparent (Gregory et al., 2007). The disease in curly-coated retrieves is mild compared to what was reported in German shepherds (Ceh et al., 1976; Rafiquzzaman et al., 1976) as a severe metabolic derangement that led to death or euthanasia by 15 months of age. This is likely due to a different mutation or genetic background.
Yi et al. (2012) provided a detailed clinical account of the disorder in Curly Coat Retrievers, having established a colony that segregates for the causal mutation described above. They summarise their findings as: " Abnormally high glycogen deposition was found in liver and muscle, and, consistent with liver and muscle damage, high and gradually increasing activity of enzymes including AST, ALT, ALP and CPK were found in serum. In muscle, increased glycogen deposition was accompanied by disruption of the contractile apparatus and fraying of myofibrils. Progressive, age-related liver fibrosis and muscle damage caused by glycogen accumulation were the major features of GSD IIIa in affected dogs."Pathology: In a normal dog, the release of glucagon stimulates the breakdown of glycogen. This breakdown happens through the work of phosphorylase and glycogen debranching enzyme. Dogs with GSD IIIa are deficient in glycogen debranching enzyme, so instead of breaking down glycogen into glucose, they accumulate abnormal glycogen particles. This mostly happens in liver and muscle, which are the tissues that have the highest levels of glycogen metabolism (Gregory et al., 2007). Livers of affected animals are dark red, enlarged, and friable, with smooth edges and a grainy surface appearance. On histologic examination, hepatocytes show global cellular swelling with diaphanous eosinophilic (foamy) cytoplasm, but no evidence of inflammation, fibrosis, or cytoplasmic fat. Glycogen accumulation is evident with PAS staining (Gregory et al., 2007). Glucose homeostasis may be sufficiently affected in times of stress to cause hypoglycemia. Control: Parents of affected dogs are obligate carriers, and siblings should be tested. Breeding of affected animals is not recommended. If a carrier must be bred, it is advised to breed that dog only to a dog that has tested as homozygous normal. Genetic testing: A test is available to detect the mutation. Breed: Curly-coated retriever. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|AGL||amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase||Canis lupus familiaris||6||NC_051810.1 (50468323..50395404)||AGL||Homologene, Ensembl, NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|466||Curly-coated retriever||Glycogen storage disease IIIa||AGL||deletion, small (<=20)||Naturally occurring variant||CanFam3.1||6||g.50050457del||c.4223del||p.(K1408Sfs*6)||NM_001048096.1; NP_001041561.1; published as c.4223delA; genomic position adjusted to HGVS 3' rule||2007||17338148||Genomic and protein coordinates in CanFam3.1 provided by Robert Kuhn|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2020||Almodóvar-Payá, A., Villarreal-Salazar, M., de Luna, N., Nogales-Gadea, G., Real-Martínez, A., Andreu, A.L., Martín, M.A., Arenas, J., Lucia, A., Vissing, J., Krag, T., Pinós, T. :|
|Preclinical research in glycogen storage diseases: A comprehensive review of current animal models. Int J Mol Sci 21:9621, 2020. Pubmed reference: 33348688. DOI: 10.3390/ijms21249621.|
|2016||Brooks, E.D., Yi, H., Austin, S.L., Thurberg, B.L., Young, S.P., Fyfe, J.C., Kishnani, P.S., Sun, B. :|
|Natural Progression of Canine Glycogen Storage Disease Type IIIa. Comp Med 66:41-51, 2016. Pubmed reference: 26884409.|
|2014||Yi, H., Brooks, E.D., Thurberg, B.L., Fyfe, J.C., Kishnani, P.S., Sun, B. :|
|Correction of glycogen storage disease type III with rapamycin in a canine model. J Mol Med (Berl) :, 2014. Pubmed reference: 24509886. DOI: 10.1007/s00109-014-1127-4.|
|2012||Yi, H., Thurberg, B.L., Curtis, S., Austin, S., Fyfe, J., Koeberl, D.D., Kishnani, P.S., Sun, B. :|
|Characterization of a canine model of glycogen storage disease type IIIa. Dis Model Mech 5:804-11, 2012. Pubmed reference: 22736456. DOI: 10.1242/dmm.009712.|
|2007||Gregory, BL., Shelton, GD., Bali, DS., Chen, YT., Fyfe, JC. :|
|Glycogen storage disease type IIIa in curly-coated retrievers. J Vet Intern Med 21:40-6, 2007. Pubmed reference: 17338148.|
|1983||Walvoort, HC. :|
|Glycogen storage diseases in animals and their potential value as models of human disease. J Inherit Metab Dis 6:3-16, 1983. Pubmed reference: 6408305.|
|1977||Otani, T., Mochizuki, H. :|
|[Glycogen storage disease (III ?) of dogs]. Jikken Dobutsu 26:172-3, 1977. Pubmed reference: 267585.|
|1976||Ceh, L., Hauge, J.G., Svenkerud, R., Strande, A. :|
|Glycogenosis type III in the dog. Acta Vet Scand 17:210-22, 1976. Pubmed reference: 181976.|
|Rafiquzzaman, M., Svenkerud, R., Strande, A., Hauge, J.G. :|
|Glycogenosis in the dog. Acta Vet Scand 17:196-209, 1976. Pubmed reference: 1066041.|
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