In other species: turkey , dog , domestic cat , horse , deer , taurine cattle , rabbit

Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 145600 (trait) , 180901 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1991

Cross-species summary: A progressive increase in body temperature, muscle rigidity and metabolic acidosis, leading to rapid death.

Species-specific name: Porcine Stress Syndrome

Species-specific symbol: PSS

Species-specific description: In pigs, malignant hyperthermia (MH) leads to rapid post-mortem changes in muscle, resulting in pale soft exudative (PSE) meat. MH can be triggered by a minor stress, such as loading, transport, sexual intercourse, high ambient temperature, or exposure to the anaesthetic halothane. Susceptibility to halothane-induced MH is an autosomal recessive trait in pigs. Together, sudden death syndrome and PSE constitute porcine stress syndrome (PSS), which became a major economic problem in many countries in the 1970s, as indicated by the number of references in the list below. In part, the increasing problem of PSS was due to strong selection for increased leanness, which is associated with susceptibility to PSS.

History: The Canadian-based research team that discovered RYR1:c.1843C>T as the likely causal variant of malignant hyperthermia (MH) in pigs was actually a team of human medical geneticists. Why was this discovery - so important in animal agriculture - made in a human genetics lab? Because these researchers were hot on the trail of likely causal variants of MH in humans, and, knowing that MH had been mapped in pigs but not in humans, the Canadian team realised that the best way to discover the cause of MH in humans was by making use of comparative mapping, i.e. assuming that the genes to which MH is linked in pigs are the same genes to which human MH is linked. Working on this supposition, the Canadian team provided the first example of a human Mendelian disorder being mapped on the basis of information gleaned from non-laboratory animals (MacLennan et al., 1990). As it happens, the same pig-mapping information was also used to map human MH by a European team of human geneticists, whose paper (McCarthy et al., 1990) was published in the same issue of Nature, immediately following the Canadian paper. As detailed by Nicholas and Hobbs (2013), in rapid succession the Canadian team of human geneticists then discovered the molecular basis of MH in pigs (Fujii et al., 1991; published in July) and in humans (Gillard et al., 1991; published in November). The really intriguing aspect of these two discoveries is that exactly the same base substitution, leading to the same amino-acid substitution in the same equivalent site of the RYR1 gene, is causative of MH in pigs (c.1843C>T; p.Arg615Cys; Fujii et al., 1991) and in humans (c.1840C>T; p.Arg614Cys; Gillard et al., 1991).

Inheritance: Autosomal recessive inheritance (with some incomplete penetrance) of malignant hyperthermia induced by halothane inhalation was reported by Ollivier et al., 1975; Minkema et al., 1977; and Smith and Bampton, 1978).

Mapping: Building on reports of association between halothane-induced malignant hyperthermia (Hal) and various gene markers, Andresen and Jensen (1977) showed that Hal is linked to the gene encoding phosphohexose isomerase (PHI), now called glucose phosphate isomerase (GPI). By the mid-1980s, this linkage group had been expanded to comprise six loci, including Hal (Archibald and Imlah, 1985). Using in situ hybridisation of a clone containing the porcine GPI gene, Davies et al. (1988) showed that the Hal linkage group maps to chromosome SSC6p12-q22. Also using in situ hybridisation, Harbitz et al. (1990) physically mapped the RYR1 gene (then called the calcium release channel [CRC] gene) to chromosome SSC6p11-q21.

Molecular basis: The molecular basis of MH in pigs was discovered via identification of a strong candidate gene, namely RYR1, that encodes a calcium release channel of skeletal muscle sarcoplasmic reticulum. When it was shown that this candidate gene mapped very closely to MH in pigs and in humans, the race was on to clone and sequence the RYR1 gene. The race was won by a Canadian research team led by David MacLennan (Fujii et al., 1991) who showed that MH is due to a base substitution (C-T) in the 1843rd nucleotide of the RYR1 gene. The base substitution causes an amino-acid substitution (arginine - cysteine) in the 615th position of the calcium release channel, resulting in altered calcium flow. It is remarkable that the smallest possible change (a single base-substitution) leading to a single amino-acid-substitution in a very large molecule (comprising 5,035 amino acids) can have caused a disorder that was a major financial burden for the global pig industry for several decades. Interestingly, Bates et al. (2012) reported that "A proportion of pigs normal for RYR1 did exhibit limb rigidity during halothane gas challenge, and subsequently tended to have lower 45 min pH and greater longissimus muscle fluid loss post harvest." This suggests that the RYR1 locus is not the only factor determining reaction to halothane.

Genetic testing: Various PCR genotyping tests have been devised, all based on detection of an RFLP resulting from the causative base substitution. Over a roughly ten-year period, these tests enabled the harmful allele to be removed from most pig populations throughout the world.

Associated gene: