Polysaccharide Storage Myopathy (PSSM) is a novel inherited glycogenosis characterized by myoplasmic accumulation of abnormal polysaccharide and clinical myopathy. We have identified a gain of function mutation in the GYS1 gene encoding the skeletal muscle is form of glycogen synthase in horses with PSSM, which results in an amino acid substitution in a highly conserved region of the enzyme. We have also identified a second, unique non-GYS1 form of PSSM in about 20% of cases. Horses are an ideal model for the study of heritable muscle disease due to extended accurate pedigrees from founder stallions, their natural athleticism which makes metabolic disease readily apparent, and the ease of performing muscle diagnostic testing. The overall goal of this project is to use both forms of PSSM to define new mechanisms regulating skeletal muscle glycogen synthase activity and glycogen metabolism in health and disease.
Specific Aim 1 of this project will identify the functional basis for the GYS1 mutation through protein expression in E. coli and GS activity measurements, and Specific Aim 2 will determine the genetic basis of the non-GYS1 form of PSSM through whole genome association mapping with SNP markers. Candidate and environment: Dr. Molly McCue has DVM, MS and PhD degrees, and is board certified in Large Animal Internal Medicine. She has secured a tenure track faculty position with a research program focusing on the clinical, epidemiologic, genetic and functional basis of large animal models of neuromuscular disease. Her short term goals are to build the skills needed to define the genetic and functional basis of disease. The training program is designed to allow Dr. McCue to develop these skills while also developing other tools needed to succeed in academic medicine. The University of Minnesota has a strong program in comparative medicine and a highly collaborative environment which will be integral to Dr. McCue's success.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Boyce, Amanda T
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University of Minnesota Twin Cities
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Avila, Felipe; Mickelson, James R; Schaefer, Robert J et al. (2018) Genome-Wide Signatures of Selection Reveal Genes Associated With Performance in American Quarter Horse Subpopulations. Front Genet 9:249
Maile, C A; Hingst, J R; Mahalingan, K K et al. (2017) A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase. Biochim Biophys Acta Gen Subj 1861:3388-3398
McCoy, Annette M; Beeson, Samantha K; Splan, Rebecca K et al. (2016) Identification and validation of risk loci for osteochondrosis in standardbreds. BMC Genomics 17:41
McCoy, A M; Ralston, S L; McCue, M E (2015) Short- and long-term racing performance of Standardbred pacers and trotters after early surgical intervention for tarsal osteochondrosis. Equine Vet J 47:438-44
McCoy, Annette M; Schaefer, Robert; Petersen, Jessica L et al. (2014) Evidence of positive selection for a glycogen synthase (GYS1) mutation in domestic horse populations. J Hered 105:163-72
Petersen, Jessica L; Mickelson, James R; Cleary, Kristen D et al. (2014) The American Quarter Horse: population structure and relationship to the thoroughbred. J Hered 105:148-62
Petersen, Jessica L; Valberg, Stephanie J; Mickelson, James R et al. (2014) Haplotype diversity in the equine myostatin gene with focus on variants associated with race distance propensity and muscle fiber type proportions. Anim Genet 45:827-35
McCoy, A M; McCue, M E (2014) Validation of imputation between equine genotyping arrays. Anim Genet 45:153
Teixeira, R B C; Rendahl, A K; Anderson, S M et al. (2013) Coat color genotypes and risk and severity of melanoma in gray quarter horses. J Vet Intern Med 27:1201-8
Petersen, Jessica L; Mickelson, James R; Cothran, E Gus et al. (2013) Genetic diversity in the modern horse illustrated from genome-wide SNP data. PLoS One 8:e54997

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