Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1993-03-15
1994-10-25
Fleisher, Mindy B.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 912, 536 2431, 536 2433, C12Q 168, C12P 1934, C07H 2104
Patent
active
053586492
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the animal disease malignant hyperthermia (MH), to the cloning and characterization of a gene associated with MH in swine, and to the development of DNA and antibody-based methods for detecting individual pigs susceptible to MH.
BACKGROUND OF THE INVENTION
Malignant hyperthermia (MH) is a hypermetabolic myopathy which is triggered in genetically-susceptible human and animal individuals by potent, volatile anesthetics such as halothane [Denborough and Lovell (1960) Lancet 2, 545: Harrison et al. (1968) Brit. Med. J. 3:594-595] or by depolarizing muscle relaxants such as succinycholine [Harrison et al. (1969) Brit. J. Anaesthesia 41:844-855]. In swine, it is also referred to as porcine stress syndrome [Topel (1968) Mod. Vet. Pract. 49:40-41; 59-60] because it may be triggered by exertional [Ludvigsen (1953) Internat. Vet. Congr. Stockholm 1:602-606] thermal [Forrest et al. (1968) J. of Appl. Physiol. 24:33-39], anoxic [Lister et al. (1970) Am. J. Physiol. 218:102-107], or mechanical [Gronert (1980) Anaesthesiol. 44:36-43] stressors as well as anesthesia [Hall et al (1966) Brit. Med. J. 4:1305]. A similar stress syndrome may occur in MH-susceptible (MHS) humans [Wingard (1974) Lancet 2;1450-1451] and dogs [O'Brien et al. (1983) Can. Vet. J. 24:172-177]. MH is characterized by the peracute development of contracture and maximal rate of metabolism in muscle. These have been proposed to occur due to an uncontrollable and sustained elevation of myoplasmic calcium [Britt and Kalow (1970) Can. Anesthetists Soc. J. 17:316-330: Lopez et al. (1985) Biophys. J. 47:313a], which is known to activate the contractile apparatus and metabolic machinery of skeletal muscle [Martonosi (1984) Physiol. Rev. 64:1240-1319).
The hyperactivity of muscle which occurs during MH results in the depletion of ATP and glycogen stores and the excessive formation of carbon dioxide, lactic acid and heat. This thermogenesis, in conjunction with peripheral vasoconstriction, leads to hyperthermia. The rapid rate of aerobic metabolism, by depleting blood oxygen, causes cyanosis [Gronert (1980) Anaesthesiol. 53:395-423]. During MH, glycogenolysis, rhabdomyolysis and acidemia cause the release of large amounts of potassium from muscle and liver [Hall et al. (1980) Brit. J. Anaesthesiol. 52:11-17 ] into the vascular compartment. The resultant hyperkalemia contributes to the development of cardiac dysrhythmia and subsequent heart failure [Britt (1983) in "Complications in Anesthesiology" F. K. Orkin and L. H. Cooperman (eds) Lippincott, pp. 290-313].
Major revenue loss in the swine, pork and bacon industries occurs because of stress-induced MH deaths, usually during transport to the slaughterhouse. This occurs in homozygotes which make up 1 to 2% of swine and is referred to as porcine stress syndrome (PSS). Greater loss occurs due to the development of inferior quality meat after slaughter of MHS homozygote or heterozygote swine, which make up 10 to 30% of the population.
Activities and environmental stressors, which may trigger MH, include transport, restraint, mating, farrowing, fighting, vigorous exercising, and hot, humid weather [Mitchell and Heffron (1982) Adv. Food Res. 28:167-230]. The neural stimulation of muscle which occurs during slaughter [McLoughlin (1971) in "Condition and Meat Quality of Pigs" G. R. Hersel-de-heer et al (eds) Pudoc, pp 123-132], and the anoxia [Lister et al (1970) Am. J. Physiol. 215:102-107] which occurs with cardiac failure, are sufficient to trigger hypermetabolism in muscle.
As a result of the excessive rates of production of lactic acid and heat [Lawrie (1960) J. Comp. Pathol. 70:273-295], sarcoplasmic proteins denature, thereby causing a deterioration of the water-binding capacity of muscle. Furthermore, the increased osmotic activity due to end-products of hypermetabolism causes an influx of water from the extracellular space, thereby resulting in hemoconcentration and increased intramyofiber water content [Berman et al (1970) Nature 220:653-655]. The muscle b
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O'Brien, "Etiopathogenetic Defec
MacLennan David H.
O'Brien Peter J.
Fleisher Mindy B.
The University of Toronto Innovations Foundation
University of Guelph
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