Comparative and Veterinary Pharmacology

eventually isolated the causative mutation (c.1649t>c; p.V547A) within the canine
RyR1gene. Interestingly, likeRyR1mutations in people and horses (but unlike pigs),
the canineRyR1c.1649t>c also showed a dominant inheritance pattern. At present
it is not known how prevalent this mutation is in the general dog population.
There have been several case reports of malignant hyperthermia in cats (de Jong
et al. 1974 ; Bellah et al. 1989 ), although the genetic basis has not been determined
in this species. A transgenic mouse model has been generated with a mutation that
is homologous to those in humans and pigs (p.R163C) (Yang et al. 2006 ). This
model appears to reproduce the majority of the pathophysiological features of the
syndrome in people.

3.2 Warfarin Resistance in Rats

Studies of resistance to warfarin toxicity in rats have served as a useful model for
understanding variability in the therapeutic anticoagulant effects of this drug in
human patients. Warfarin and related anticoagulants have been used as rodenticides
for over 50 years. However, currently as many as 75% of wild rats show signs of

Human

Rabbit

Pig

Dog

Horse

MH horse

2442

2442

2443

492

L Q A G K G E A L R R A I L R S L V P L E D L V G I S L P L Q P T L G K

L Q A G K G E A L R R A I L R S L V P L E D L V G I S L P L Q P T L G K

L Q A G K G E A L R R A I L R S L V P L E D L V G I S L P L Q P T L G K

L Q A G K G E A L R R A I L R S L V P L E D L V G I S L P L Q P T L G K

L Q A G K G E A L R R A I L R S L V P L E D L V G I S L P L Q P T L G K

L Q A G K G E A L R G A I L R S L V P L D D L V G I S L P L Q P T L G K

aa aa

C T CCCCCT GGG A TTG G A

7360

(^7349) A N 7367
2481
2481
2482
531
Fig. 6Identification of a genetic polymorphism in exon 46 of the equineRyR1gene associated
with malignant hyperthermia in Quarter horses (from (Aleman et al. 2004 )).Bottom panelshows
the sequencing chromatogram of cDNA from an affected horse that is heterozygous for C and G
alleles at position 7360. As shown in thetop panel,this mutation is predicted to result in
substitution of a highly species conserved arginine (R) by a glycine (G) at amino acid position
2454, with possible effects on RyR1 function
Comparative and Veterinary Pharmacogenomics 69