Glycogen storage disease type Ia in canines: a model for human metabolic and genetic liver disease

Abstract

A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including "lactic acidosis", larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.

Figure 1

PCR sequencing and restriction digest for the canine mutation. (a) Sequencing chromatogram of the mutation region showing the G450C transversion on both alleles of an affected dog (−/−) and on one allele in a heterozygote (+/−). (b) Ncol digest after amplification of the target region resulting in cutting of the wild-type alleles (+/+), cutting of one allele in the heterozygote (+/−), and larger undigested bands from both alleles in the homozygous dog (−/−).

Figure 2

Outline of endogenous glucose production pathways. EC = extracellular, IC = intracellular. (a) Normal pathway and function of G6Pase. (b) Alterations seen with deficiency of G6Pase (GSDIa) include lack of dephosphorylation of G6P and shunting of excess G6P to produce glycogen and lactate.