OMIA:000418-9615 : Glycogen storage disease Ia in Canis lupus familiaris (dog)

Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 232200 (trait) , 613742 (gene)

Links to relevant human diseases in MONDO:

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1997

Species-specific description: Glycogen storage disease I is a severe disorder of glycogen metabolism characterized by glycogen accumulation, particularly in the liver. Signs include severe hepatomegaly, failure to thrive, coma, and death. There is a genetic test available.

Mapping: CFA9

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Kishnani et al. (1997) showed that the causative mutation in [Maltese Terrier] dogs is a G to C transversion in the G6PC (glucose-6-phosphatase) gene that changes the amino acid codon from methionine to isoleucine (M121I), producing a variant of the enzyme with "15 times less enzyme activity". Christen et al. (2021) conducted whole genome sequencing in one of two affected purebred German Pinscher puppies and "revealed a homozygous 76 bp insertion into exon 5 of the G6PC1 candidate gene, which probably causes a loss of function (chr9:g.20,134,857_20,134,858ins76; XM_038676372.1:c.634_635ins76). The insertion consisted of 60 consecutive adenines and an additional 16 bp duplication of the integration site ... ."

Clinical features: Affected animals are hypoglycemic if fasted, and develop lactic acidosis, hypertriglyceridemia, and hyperuricemia (Specht et al., 2011). Signs include severe hepatomegaly, poor body condition, lethargy, failure to thrive, coma, and death.

Pathology: Glucose-6-phosphate catalyzes the production of glucose from glucose-6-phosphate. The mutant G6PC has 15 times less activity than the normal enzyme (Kishnani et al., 1997) and decreased amounts in the liver and kidney (Kishnani et al., 2001). Affected dogs develop severe hypoglycemia, glycogen storage, and progressive hepatomegaly. Hepatocytes are diffusely vacuolated, containing large quantities of glycogen. Soft tissue mineralization can occur in renal tubules and pulmonary alveolar septa (Brix et al., 1995).

Prevalence: Christen et al. (2021) genotyped 208 German Pinscher dogs for the German Pinscher variant and identified a carrier frequency of 12%.

Control: Parents and siblings of affected dogs should be tested. Mating that could result in affected dogs should be avoided. Arnson et al. (2023) "attempted genome editing ... in a dog model for GSD Ia. We demonstrated donor transgene integration in the liver of three adult-treated dogs accompanied by stable G6Pase expression and correction of hypoglycemia during fasting. Two puppies with GSD Ia were treated by genome editing that achieved donor transgene integration in the liver. Integration frequency ranged from 0.5% to 1% for all dogs. ... Thus, genome editing can integrate a therapeutic transgene in the liver of a large animal model, either early or later in life, and further development is warranted to provide a more stable treatment for GSD Ia." (This study involves genetically modified organisms (GMO).

Genetic testing: The base substitution in Maltese Terriers removes an NcoI restriction site, thereby enabling a simple RFLP PCR test to detect carriers.

Breeds: German Pinscher (Dog) (VBO_0201454), Maltese Terrier (Dog) (VBO_0200859).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
G6PC glucose-6-phosphatase, catalytic subunit Canis lupus familiaris 9 NC_051813.1 (20862184..20851596) G6PC Homologene, Ensembl , NCBI gene


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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 Year Published PubMed ID(s) Acknowledgements
1361 German Pinscher (Dog) Glycogen storage disease Ia G6PC insertion, gross (>20) Naturally occurring variant CanFam3.1 9 g.20134857_20134858insN[76] c.634_635insN[76] XM_038676372.1; insertion of 60 consecutive adenines and an additional 16 bp duplication of the integration site (Christen et al., 2021) 2021 34610166
44 Maltese (Dog) Glycogen storage disease Ia G6PC missense Naturally occurring variant CanFam3.1 9 g.20138777C>G c.363G>C p.(M121I) NM_001002993.2; NP_001002993.2; published as c.450G>C; coordinates in the table have been updated to a recent reference genome and / or transcript 1997 9259982 Genomic coordinates in CanFam3.1 provided by Robert Kuhn

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2023). OMIA:000418-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset].


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.

2023 Arnson, B., Kang, H.R., Brooks, E.D., Gheorghiu, D., Ilich, E., Courtney, D., Everitt, J.I., Cullen, B.R., Koeberl, D.D. :
Genome editing using Staphylococcus aureus Cas9 in a canine model of glycogen storage disease Ia. Mol Ther Methods Clin Dev 29:108-119, 2023. Pubmed reference: 37021039. DOI: 10.1016/j.omtm.2023.03.001.
Chandler, R.J. :
From Puppies to adults: <i>In vivo</i> editing of hepatocytes in a canine model of glycogen storage disease type Ia. Mol Ther Methods Clin Dev 29:347-349, 2023. Pubmed reference: 37206367. DOI: 10.1016/j.omtm.2023.04.006.
2022 Petrova, I.O., Smirnikhina, S.A. :
Studies on glycogen storage disease type 1a animal models: a brief perspective. Transgenic Res 31:593-606, 2022. Pubmed reference: 36006546. DOI: 10.1007/s11248-022-00325-7.
2021 Christen, M., Reineking, W., Beineke, A., Jagannathan, V., Baumgärtner, W., Leeb, T. :
Polyadenine insertion disrupting the G6PC1 gene in German Pinschers with glycogen storage disease type Ia (GSD1A). Anim Genet 52:900-902, 2021. Pubmed reference: 34610166. DOI: 10.1111/age.13146.
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.
2019 Kang, H.R., Gjorgjieva, M., Smith, S.N., Brooks, E.D., Chen, Z., Burgess, S.M., Chandler, R.J., Waskowicz, L.R., Grady, K.M., Li, S., Mithieux, G., Venditti, C.P., Rajas, F., Koeberl, D.D. :
Pathogenesis of hepatic tumors following gene therapy in murine and canine models of glycogen storage disease. Mol Ther Methods Clin Dev 15:383-391, 2019. Pubmed reference: 31890731. DOI: 10.1016/j.omtm.2019.10.016.
2018 Brooks, E.D., Landau, D.J., Everitt, J.I., Brown, T.T., Grady, K.M., Waskowicz, L., Bass, C.R., D'Angelo, J., Asfaw, Y.G., Williams, K., Kishnani, P.S., Koeberl, D.D. :
Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy. J Inherit Metab Dis 41:965-76, 2018. Pubmed reference: 30043186. DOI: 10.1007/s10545-018-0223-y.
Lee, Y.M., Conlon, T.J., Specht, A., Coleman, K.E., Brown, L.M., Estrella, A.M., Dambska, M., Dahlberg, K.R., Weinstein, D.A. :
Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia. J Inherit Metab Dis 41:977-984, 2018. Pubmed reference: 29802554. DOI: 10.1007/s10545-018-0199-7.
2013 Brooks, E.D., Little, D., Arumugam, R., Sun, B., Curtis, S., Demaster, A., Maranzano, M., Jackson, M.W., Kishnani, P., Freemark, M.S., Koeberl, D.D. :
Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia. Mol Genet Metab 109:161-70, 2013. Pubmed reference: 23623482. DOI: 10.1016/j.ymgme.2013.03.018.
2012 Demaster, A., Luo, X., Curtis, S., Williams, K.D., Landau, D.J., Drake, E.J., Kozink, D.M., Bird, A., Crane, B., Sun, F., Pinto, C.R., Brown, T.T., Kemper, A.R., Koeberl, D.D. :
Long-term efficacy following readministration of an adeno-associated virus vector in dogs with glycogen storage disease type Ia. Hum Gene Ther 23:407-18, 2012. Pubmed reference: 22185325. DOI: 10.1089/hum.2011.106.
Koeberl, D.D. :
In search of proof-of-concept: gene therapy for glycogen storage disease type Ia. J Inherit Metab Dis 35:671-8, 2012. Pubmed reference: 22310927. DOI: 10.1007/s10545-012-9454-5.
2011 Crane, B., Luo, X., Demaster, A., Williams, KD., Kozink, DM., Zhang, P., Brown, TT., Pinto, CR., Oka, K., Sun, F., Jackson, MW., Chan, L., Koeberl, DD. :
Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia. Gene Ther 19:443-52, 2011. Pubmed reference: 21654821. DOI: 10.1038/gt.2011.86.
Specht, A., Fiske, L., Erger, K., Cossette, T., Verstegen, J., Campbell-Thompson, M., Struck, MB., Lee, YM., Chou, JY., Byrne, BJ., Correia, CE., Mah, CS., Weinstein, DA., Conlon, TJ. :
Glycogen storage disease type Ia in canines: a model for human metabolic and genetic liver disease. J Biomed Biotechnol 2011:646257, 2011. Pubmed reference: 21318173. DOI: 10.1155/2011/646257.
2010 Weinstein, DA., Correia, CE., Conlon, T., Specht, A., Verstegen, J., Onclin-Verstegen, K., Campbell-Thompson, M., Dhaliwal, G., Mirian, L., Cossette, H., Falk, DJ., Germain, S., Clement, N., Porvasnik, S., Fiske, L., Struck, M., Ramirez, HE., Jordan, J., Andrutis, K., Chou, JY., Byrne, BJ., Mah, CS. :
Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia. Hum Gene Ther 21:903-10, 2010. Pubmed reference: 20163245. DOI: 10.1089/hum.2009.157.
2009 Koeberl, D.D., Pinto, C., Brown, T., Chen, Y.T. :
Gene therapy for inhereted metabolic disorders in companion animals. ILAR J 50:122-7, 2009. Pubmed reference: 19293457. DOI: 10.1093/ilar.50.2.122.
2008 Koeberl, DD., Pinto, C., Sun, B., Li, S., Kozink, DM., Benjamin, DK., Demaster, AK., Kruse, MA., Vaughn, V., Hillman, S., Bird, A., Jackson, M., Brown, T., Kishnani, PS., Chen, YT. :
AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia. Mol Ther 16:665-72, 2008. Pubmed reference: 18362924. DOI: 10.1038/mt.2008.15.
2002 Beaty, R.M., Jackson, M., Peterson, D., Bird, A., Brown, T., Benjamin, D.K., Juopperi, T., Kishnani, P., Boney, A., Chen, Y.T., Koeberl, D.D. :
Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors Gene Therapy 9:1015-1022, 2002. Pubmed reference: 12101432. DOI: 10.1038/
2001 Kishnani, P.S., Faulkner, E., VanCamp, S., Jackson, M., Brown, T., Boney, A., Koeberl, D., Chen, Y.T. :
Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia) Veterinary Pathology 38:83-91, 2001. Pubmed reference: 11199168.
1997 Kishnani, P.S., Bao, Y., Wu, J.Y., Brix, A.E., Lin, J.L., Chen, Y.T. :
Isolation and nucleotide sequence of canine glucose-6-phosphatase mRNA: identification of mutation in puppies with glycogen storage disease type Ia. Biochem Mol Med 61:168-77, 1997. Pubmed reference: 9259982. DOI: 10.1006/bmme.1997.2600.
1995 Brix, A.E., Howerth, E.W., Mcconkierosell, A., Peterson, D., Egnor, D., Wells, M.R., Chen, Y.T. :
Glycogen storage disease type Ia in two littermate maltese puppies Veterinary Pathology 32:460-465, 1995. Pubmed reference: 8578635.

Edit History

  • Created by Frank Nicholas on 12 Sep 2005
  • Changed by Vicki Meyers-Wallen on 10 Sep 2011
  • Changed by Vicki Meyers-Wallen on 14 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 03 Sep 2012
  • Changed by Imke Tammen2 on 08 Oct 2021
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