Characterization of a canine model of glycogen storage disease type IIIa

Haiqing Yi,Beth L Thurberg,Priya S Kishnani,Sarah Curtis,Stephanie Austin,Dwight D Koeberl,Baodong Sun,John Fyfe

doi:10.1242/dmm.009712

Abstract

SUMMARYGlycogen storage disease type IIIa (GSD IIIa) is an autosomal recessive disease caused by deficiency of glycogen debranching enzyme (GDE) in liver and muscle. The disorder is clinically heterogeneous and progressive, and there is no effective treatment. Previously, a naturally occurring dog model for this condition was identified in curly-coated retrievers (CCR). The affected dogs carry a frame-shift mutation in the GDE gene and have no detectable GDE activity in liver and muscle. We characterized in detail the disease expression and progression in eight dogs from age 2 to 16 months. Monthly blood biochemistry revealed elevated and gradually increasing serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities; serum creatine phosphokinase (CPK) activity exceeded normal range after 12 months. Analysis of tissue biopsy specimens at 4, 12 and 16 months revealed abnormally high glycogen contents in liver and muscle of all dogs. Fasting liver glycogen content increased from 4 months to 12 months, but dropped at 16 months possibly caused by extended fibrosis; muscle glycogen content continually increased with age. Light microscopy revealed significant glycogen accumulation in hepatocytes at all ages. Liver histology showed progressive, age-related fibrosis. In muscle, scattered cytoplasmic glycogen deposits were present in most cells at 4 months, but large, lake-like accumulation developed by 12 and 16 months. Disruption of the contractile apparatus and fraying of myofibrils was observed in muscle at 12 and 16 months by electron microscopy. In conclusion, the CCR dogs are an accurate model of GSD IIIa that will improve our understanding of the disease progression and allow opportunities to investigate treatment interventions.

Highlights

Mutations in glycogen debranching enzyme (GDE) gene cause glycogen storage disease type III (GSD III), resulting in accumulation of cytoplasmic glycogen in liver and muscle, the two major tissues for glycogen metabolism (Illingworth and Cori, 1952; Illingworth et al, 1956)
The authors characterized in detail the expression and progression of GSD IIIa in affected curly-coated retrievers (CCR)
High glycogen deposition was found in liver and muscle, and, consistent with liver and muscle damage, high and gradually increasing activity of enzymes including aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and creatine phosphokinase (CPK) were found in serum

Summary

Introduction

Mutations in glycogen debranching enzyme (GDE) gene cause glycogen storage disease type III (GSD III), resulting in accumulation of cytoplasmic glycogen in liver and muscle, the two major tissues for glycogen metabolism (Illingworth and Cori, 1952; Illingworth et al, 1956). GDE is responsible for complete degradation of cytoplasmic glycogen. More than 80% of GSD III patients have debranching enzyme deficiencies in both liver and muscle (type IIIa), and most of the rest manifest only liver involvement (type IIIb) (Van Hoof and Hers, 1967; Kishnani et al, 2010). Disease phenotypes vary widely in patients, most probably caused by different GDE mutations specific to individual families on Received 22 February 2012; Accepted 25 May 2012

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