In other species: dog , domestic cat

Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 232500 (trait) , 607839 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009292: glycogen storage disease due to glycogen branching enzyme deficiency

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2004

Cross-species summary: Glycogen storage disease caused by glycogen branching enzyme (GBE) deficiency

Species-specific name: Glycogen storage disease IV (GSD IV); glycogen storage disease (GSD); glycogen branching enzyme deficiency (GBED); amylopectinosis

Species-specific description: A deficiency in the glycogen branching enzyme (GBE1) is responsible for the autosomal recessive disease in American Quarter Horses initially identified as GSD and later termed GBED or Glycogen Storage Disease IV (GSD IV) after a homologous condition in people. This genetic mutation leads to the inability to mobilize glycogen leading to decreased levels of glucose in the blood and ultimately organ failure leading to death (Valberg et al., 2001; Ward et al., 2004). [IT thanks Elizabeth Clark, working under the guidance of Professor Ernie Bailey, for contributions to this entry in April 2022]

Mapping: Ward et al. (2004): "We .... mapped the GBE1 gene to equine chromosome 26 (ECA26q12–q13) and confirmed it as a candidate gene for GSD IV by microsatellite marker allele association (Ward et al. 2003)."

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on biochemical and histopathological evidence relating to the homologous disorder in other species), Ward et al. (2004) showed that this disorder in American Quarter horses is due to a c.102C>A base substitution in exon 1 of the GBE1 gene encoding glycogen branching enzyme, resulting in a p.(Y34X) nonsense mutation. Tryon et al. (2009) screened American Quarter horses and American Paint horses for likely causal variants for several conditions and identified that the GBE1 c.102C>A variant is present in the American Paint horse population.

Clinical features: Valberg et al. (2001) investigated “related Quarter Horse foals that died by 7 weeks of age … . Clinical signs varied from stillbirth, transient flexural limb deformities, seizures, and respiratory or cardiac failure to persistent recumbency. Leukopenia … as well as high serum creatine kinase … , aspartate transaminase … , and gamma glutamyl transferase … activities were present in most foals, and intermittent hypoglycemia was present in 2 foals.“

Pathology: Valberg et al. (2001): “Gross postmortem lesions were minor, except for pulmonary edema in 2 foals. Muscle, heart, or liver samples from the foals contained abnormal periodic acid Schiff's (PAS)-positive globular or crystalline intracellular inclusions … . Accumulation of an unbranched polysaccharide in tissues was suggested by a shift in the iodine absorption spectra of polysaccharide isolated from the liver and muscle of affected foals. Skeletal muscle total polysaccharide concentrations were reduced ... , but liver and cardiac muscle glycogen concentrations were normal. Several glycolytic enzyme activities were normal, whereas GBE activity was virtually absent in ... affected foals. GBE activities in peripheral blood cells of dams of affected foals and several of their half-siblings or full siblings were approximately 50% of controls. GBE protein in liver ... was markedly reduced to absent in affected foals, and in a half-sibling of an affected foal, it was approximately one-half the amount of normal controls.”

Breeds: American Paint (Horse) (VBO_0000897), Quarter Horse (Horse) (VBO_0001057).
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: