A defect in dystrophin causes a novel porcine stress syndrome

Abstract

BackgroundLosses of slaughter-weight pigs due to transport stress are both welfare and economic concerns to pork producers. Historically, the HAL-1843 mutation in ryanodine receptor 1 was considered responsible for most of the losses; however, DNA testing has effectively eliminated this mutation from commercial herds. We identified two sibling barrows in the USMARC swine herd that died from apparent symptoms of a stress syndrome after transport at 12 weeks of age. The symptoms included open-mouth breathing, skin discoloration, vocalization and loss of mobility.ResultsWe repeated the original mating along with sire-daughter matings to produce additional offspring. At 8 weeks of age, heart rate and electrocardiographs (ECG) were monitored during isoflurane anesthesia challenge (3% for 3 min). Four males from the original sire-dam mating and two males from a sire-daughter mating died after one minute of anesthesia. Animals from additional litters were identified as having a stress response, sometimes resulting in death, during regular processing and weighing. Affected animals had elevated plasma creatine phosphokinase (CPK) levels before and immediately after isoflurane challenge and cardiac arrhythmias. A pedigree containing 250 pigs, including 49 affected animals, was genotyped with the Illumina PorcineSNP60 Beadchip and only one chromosomal region, SSCX at 25.1-27.7 Mb over the dystrophin gene (DMD), was significantly associated with the syndrome. An arginine to tryptophan (R1958W) polymorphism in exon 41 of DMD was the most significant marker associated with stress susceptibility. Immunoblots of affected heart and skeletal muscle showed a dramatic reduction of dystrophin protein and histopathology of affected hearts indicated muscle fiber degeneration.ConclusionsA novel stress syndrome was characterized in pigs and the causative genetic factor most likely resides within DMD that results in less dystrophin protein and cardiac abnormalities that can lead to death under stressful conditions. The identification of predictive markers will allow us to determine the prevalence of this disease in commercial swine populations. This defect also provides a unique biomedical model for human cardiomyopathy associated with muscular dystrophy that may be superior to those available because of the similarities in anatomy and physiology and allow advances in gene therapies for human disease.

Comparative Genomics of X-linked Muscular Dystrophies: The Golden Retriever Model

“…Several animal models of the disease exist, including the dystrophin-deficient mdx mouse [77, 78], and feline [79] and canine X-linked models of muscular dystrophy [80-90]. Dystrophin deficiency affecting cardiac and skeletal muscle has also been described in swine [91] but little information has been published regarding the causal mutation and the associated phenotype.…”

Background Pathological Changes in Minipigs

“…However, there has been a newly identified mutation in the dystrophin gene which leads to loss of animals due to transport stress, and pathological findings are similar to porcine stress syndrome (Nonneman et al 2012).…”

Biology and Diseases of Swine

“…Genotypic analyses have indicated that the mutation arose from a single founder animal. However, a newly identified mutation (R1958W) in the dystrophin gene has recently been shown to be responsible for loss of animals due to transport stress (Nonneman et al, 2012). The mode of inheritance is autosomal recessive with variable penetrance.…”

“…Lesions in animals with the dystrophin mutations consist of cardiomyofiber degeneration (Nonneman et al, 2012). In addition, many of the animals will have muscles that appear very pale and are very soft, almost watery in texture, due to the high lactic acid content in muscles that occurs postmortem.…”