recognised that PSS/PSE might represent a form of malignant hyperthermia, as
affected pigs also responded to inhalant anaesthetics with symptoms that typified
malignant hyperthermia in people (Berman et al. 1970 ). Laboratory studies using
muscle from affected pigs revealed an altered sensitivity to the effects of ryanodine
(Mickelson et al. 1988 ). Ryanodine is a toxic plant alkaloid derived from the South
American plantRyania speciosa.The alkaloid specifically binds to and partially
activates a ligand-gated calcium channel located in the sarcoplasmic reticulum
referred to as the ryanodine receptor (Xu et al. 1998 ). Subsequent sequencing of
the gene encoding the type-1 (skeletal muscle) ryanodine receptor (RyR1) located
on porcine chromosome 6q11-q12 identified the causal variant for porcine malig-
nant hyperthermia, an exon 17 coding region mutation (c.1843c>t) that results in a
cysteine for arginine substitution at amino acid 615 (p.C615R) (Fujii et al. 1991 ).
Interestingly, the first mutation associated with malignant hyperthermia in
humans was also located in exon 17 of theRyR1gene on the orthologous human
chromosome 19q13.1 with a c.1840c>t that results in a similar p.C614R amino acid
substitution (Gillard et al. 1991 ). AlthoughRyR1c.1840c>t is present in as many as
5% of identified malignant hyperthermia susceptible human patients, currently there
are over 100 different (in most cases spontaneous) mutations that account for the
remaining 95% of cases (Robinson et al. 2006 ). Several other genes have also been
implicated in human malignant hyperthermia, includingCACNA1Swhich encodes
the alpha subunit of the L-type voltage gated calcium channel also located in
skeletal muscle and associates with the ryanodine receptor (Stewart et al. 2001 ).
TheRyR1c.1843c>t variant is the only variant to date that has been associated
with porcine stress syndrome and malignant hyperthermia in pigs. It seems to have
arisen from a single founder animal and has been distributed amongst various pig
breeds of commercial significance, including Landrace, Pietrain, Yorkshire, Duroc,
and Poland China (Fujii et al. 1991 ). PorcineRyR1c.1843c>t is also referred to as
HAL-1843, because a common phenotyping method to identify affected pigs is to
observe the animal for clinical signs following exposure to a small amount of
halothane, an inhalant anaesthetic and trigger agent (Ritter et al. 2008 ). The
“halothane challenge test” has been used in an attempt to identify affected animals
to avoid costly losses associated with deaths during shipping prior to slaughter.
However,RyR1c.1843c>t has been proposed to be more accurate than the “halo-
thane challenge test” for this purpose (Rempel et al. 1993 ). A recent (2008)
genotyping survey indicates that 11% of commercial piggeries in the USA have
pigs with this variant (Ritter et al. 2008 ).
An interesting difference between the humanRyR1c.1840c>t and the pigRyR1
c.1843c>t variants is that the pig mutation is recessive (two alleles are needed for
malignant hyperthermia phenotype), while the human mutation is dominant (only one
allele is needed for malignant hyperthermia phenotype) (Zhou et al. 2006 ). Recent
work suggests that the humanRyR1gene is regulated through epigenetic silencing,
such that non-mutated gene copy is transcriptionally silent allowing predominant
effects of the mutant protein (Zhou et al. 2006 ). Although two copies of the pigRyR1
c.1843c>t appear to be needed for malignant hyperthermia susceptibility and fulmi-
nant porcine stress syndrome, heterozygous animals show advantageous properties
Comparative and Veterinary Pharmacogenomics 67