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Glycogen branching enzyme (GBE1) mutation causing equine glycogen storage disease IV


Comparative biochemical and histopathological evidence suggests that a deficiency in the glycogen branching enzyme, encoded by the GBE1 gene, is responsible for a recently identified recessive fatal fetal and neonatal glycogen storage disease (GSD) in American Quarter Horses termed GSD IV. We have now derived the complete GBE1 cDNA sequences for control horses and affected foals, and identified a C to A substitution at base 102 that results in a tyrosine (Y) to stop (X) mutation in codon 34 of exon 1. All 11 affected foals were homozygous for the X34 allele, their 11 available dams and sires were heterozygous, and all 16 control horses were homozygous for the Y34 allele. The previous findings of poorly branched glycogen, abnormal polysaccharide accumulation, lack of measurable GBE1 enzyme activity and immunodetectable GBE1 protein, coupled with the present observation of abundant GBE1 mRNA in affected foals, are all consistent with the nonsense mutation in the 699 amino acid GBE1 protein. The affected foal pedigrees have a common ancestor and contain prolific stallions that are likely carriers of the recessive X34 allele. Defining the molecular basis of equine GSD IV will allow for accurate DNA testing and the ability to prevent occurrence of this devastating disease affecting American Quarter Horses and related breeds.

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Financial support for this research was provided by grants to Drs. Mickelson and Valberg from the American Quarter Horse Association, the University of Minnesota Equine Center and Minnesota Racing Commission, and the University of Minnesota Agricultural Experiment Station. The authors wish to thank Ms. Louise Petit (Animal Health Trust) for technical support and Drs. Cecilia Penedo (University of California-Davis), Jon Beever (University of Illinois), John Fyfe (Michigan State University), and John Cannon (University of Missouri) for sharing reagents, time, and technical advice during the course of this project. We also wish to thank referring veterinarians for identifying possible cases of affected foals and sampling related horses.

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Correspondence to James R. Mickelson.

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The nucleotide sequence data reported in this article have been submitted to GenBank and have been assigned the accession numbers AY505107–AY505110.

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Ward, T.L., Valberg, S.J., Adelson, D.L. et al. Glycogen branching enzyme (GBE1) mutation causing equine glycogen storage disease IV. Mamm Genome 15, 570–577 (2004).

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  • Reverse Transcription Polymerase Chain Reaction
  • Glycogen Storage Disease
  • Epidermolysis Bullosa
  • Control Horse
  • Junctional Epidermolysis Bullosa