Our long-term research goals are to develop genetic tests for equine muscle diseases including PSSM2, RER, dystrophic and non-dystrophic myotonia and some forms of malignant hyperthermia that allow horse owners, veterinarians and breeders to:
- Identify individuals at risk for developing muscle disease prior to the onset of clinical signs, allowing early intervention and informed breeding decisions; and
- Identify the functional alleles underlying these diseases, allowing for a deeper understanding of how these mutations disrupt normal muscle function, which will eventually allow us to develop specific targeted therapies.
Nearly half of the 7.2 million horses in the US are obligate athletes, used for racing, showing or agriculture work (American Horse Council 2017). Because the value of these horses depends on their athletic performance, health problems such as muscle diseases that affect their ability to train and race can have large economic consequences. The importance of these athletic phenotypes has motivated horse breeding for centuries as horses are the only domesticated species that have been highly selected for athletic phenotypes, such as an ability to sprint short distances, pull heavy loads, or compete in endurance races9.
The intense selection for these performance traits has resulted in positive selection for alleles that enhance muscle mass and performance, such as a myostatin SINE insertion that leads to increased muscle mass and improved sprinting ability10,11,12. Intense selection for muscle phenotypes may also underlie the surprisingly large number of heritable muscle diseases in horses, including HYPP, PSSM1 and PSSM2, RER, MH, IMM, MFM, dystrophic and non-dystrophic myotonia, and mitochondrial myopathy4,6,13–18. The recognition of multiple genetic muscle diseases in horses may be in part because even minor disturbances in muscle function, such as defects in energy metabolism, contractility, excitation-contraction coupling, molecular structure, or muscle repair, are readily apparent in horses that are exercised on a daily basis19,20.
Although mutations have been identified for HYPP, MH, PSSM1, mitochondrial myopathy and IMM 2,4,13,3, these mutations fail to explain a significant portion of, and the variability in, genetic muscle disease in horses17. In other words, our understanding of the basic causes of muscle disease in the horse is still evolving. And, while HYPP, MH, PSSM1, and IMM are considered Mendelian traits caused by single gene mutations, they can have incomplete penetrance or interactions with other genes and alleles (both known and unknown). The other fraction of unexplained muscle disease constitutes a category of complex conditions; some combined together into catch-all names (such as RER and PSSM2) with multiple alleles and environmental influences both contributing to the development of clinical muscle disease.
To read more about our work on specific muscle diseases follow the links below:
What about the commercially available genetic tests for PSSM2, MFM and RER?
Recently, a private company, EquiSeq, has marketed a group of single-gene genetic tests to diagnose PSSM2/MFM and RER. However, documenting the role of a particular genetic allele in disease requires several types of scientific evidence (see Studying Equine Genetic Diseases. As of yet, there are no public data or published studies associating these new alleles with muscle disease in well-phenotyped horses, and no functional evidence demonstrating that these alleles cause disease. Therefore, we have initiated a study to confirm or refute the role of the mutations that are part of EquiSeq’s muscle disease panel. More information about this study can be found here.
- McCue ME, Valberg SJ, Miller MB, et al. Glycogen synthase (GYS1) mutation causes a novel skeletal muscle glycogenosis. Genomics. 2008;doi:10.101. doi:10.1016/j.ygeno.2008.01.011.
- Aleman M, Riehl J, Aldridge BM, LeCouteur RA, Stott JL, Pessah IN. Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia. Muscle Nerve. 2004;30(3):356-365. http://www.ncbi.nlm.nih.gov/pubmed/15318347.
- Finno CJ, Gianino G, Perumbakkam S, et al. A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses. Skelet Muscle. 2018;8(1):7. doi:10.1186/s13395-018-0155-0.
- Rudolph JA, Spier SJ, Byrns G, Rojas C V, Bernoco D, Hoffman EP. Periodic paralysis in quarter horses: a sodium channel mutation disseminated by selective breeding. Nat Genet. 1992;2(2):144-147. http://www.ncbi.nlm.nih.gov/pubmed/1338908.
- McCue ME, Valberg SJ, Lucio M, Mickelson JR. Glycogen synthase 1 (GYS1) mutation in diverse breeds with polysaccharide storage myopathy. JVetInternMed. 2008;22(5):1228-1233. http://www.ncbi.nlm.nih.gov/pubmed/18691366.
- Valberg SJ, McKenzie EC, Eyrich L V., Shivers J, Barnes NE, Finno CJ. Suspected myofibrillar myopathy in Arabian horses with a history of exertional rhabdomyolysis. Equine Vet J. 2016;48(5):548-556. doi:10.1111/evj.12493.
- Fritz KL, McCue ME, Valberg SJ, Rendahl AK, Mickelson JR. Genetic mapping of recurrent exertional rhabdomyolysis in a population of North American Thoroughbreds. Anim Genet. 2012;43(6):730-738. http://www.ncbi.nlm.nih.gov/pubmed/22497487.
- Council AH. Horse Industry Statistics.; 2005.
- Petersen JL, Mickelson JR, Rendahl AK, et al. Genome-Wide Analysis Reveals Selection for Important Traits in Domestic Horse Breeds. PLoS Genet. 2013;9(1):e1003211. doi:doi:10.1371/journal.pgen.1003211.
- Binns MM, Boehler DA, Lambert DH. Identification of the myostatin locus (MSTN) as having a major effect on optimum racing distance in the Thoroughbred horse in the USA. Anim Genet. 2010;41:154-158. doi:10.1111/j.1365-2052.2010.02126.x.
- Petersen JL, Mickelson JR, Rendahl AK, et al. Genome-Wide Analysis Reveals Selection for Important Traits in Domestic Horse Breeds. PLoS Genet. 2013;9(1). doi:10.1371/journal.pgen.1003211.
- Dall’Olio S, Wang Y, Sartori C, Fontanesi L, Mantovani R. Association of myostatin (MSTN) gene polymorphisms with morphological traits in the italian heavy draft horse breed. Livest Sci. 2014;160(1):29-36. doi:10.1016/j.livsci.2013.12.002.
- McCue ME, Valberg SJ, Miller MB, et al. Glycogen synthase (GYS1) mutation causes a novel skeletal muscle glycogenosis. Genomics. 2008;91(5). doi:10.1016/j.ygeno.2008.01.011.
- Naylor RJ, Livesey L, Schumacher J, et al. Allele copy number and underlying pathology are associated with subclinical severity in equine type 1 polysaccharide storage myopathy (PSSM1). PLoSOne. 2012;7(7):e42317. http://www.ncbi.nlm.nih.gov/pubmed/22860112.
- Lentz LR, Valberg SJ, Balog EM, Mickelson JR, Gallant EM. Abnormal regulation of muscle contraction in horses with recurrent exertional rhabdomyolysis. AmJVetRes. 1999;60(8):992-999. http://www.ncbi.nlm.nih.gov/pubmed/10451211.
- Valberg SJ, Carlson GP, Cardinet III GH, et al. Skeletal muscle mitochondrial myopathy as a cause of exercise intolerance in a horse. Muscle Nerve. 1994;17(3):305-312. http://www.ncbi.nlm.nih.gov/pubmed/8107707.
- McCue ME, Valberg SJ, Lucio M, Mickelson JR. Glycogen synthase 1 (GYS1) mutation in diverse breeds with polysaccharide storage myopathy. J Vet Intern Med. 2008;22(5). doi:10.1111/j.1939-1676.2008.0167.x.
- Lewis SS, Valberg SJ, Nielsen IL. Suspected immune-mediated myositis in horses. JVetInternMed. 2007;21(3):495-503. http://www.ncbi.nlm.nih.gov/pubmed/17552457.
- Valberg SJ. Muscular causes of exercise intolerance in horses. Vet Clin North Am Equine Pract. 1996;12:495-515.
- Valberg SJ, MacLeay JM, Billstrom JA, Hower-Moritz MA, Mickelson JR. Skeletal muscle metabolic response to exercise in horses with “tying-up” due to polysaccharide storage myopathy. Equine VetJ. 1999;31(1):43-47. http://www.ncbi.nlm.nih.gov/pubmed/9952328.