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:

• MONDO:0009287: glycogen storage disease due to glucose-6-phosphatase deficiency type IA

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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: