ABSTRACT
The autosomal recessive gene, now designated as cp (corpulent), was first isolated by Simon Koletsky (1973) in a cross between rats of the Sprague Dawley strain (a very common albino rat) and the SHR (spontaneously hypertensive rat) strain, another mutation that arose in the Wistar colony at Kyoto University in Japan. Rats that were homozygous for the cp gene (cp/cp) were not only obese, but were hypertensive and exhibited a malignant atherosclerosis that was accompanied by the development of aortic aneurysms (Koletsky, 1975). In addition, male cp/cp rats had a lifespan of only some 10 months. Rats heterozygous (cp/+) or homozygous normal (+/+) were lean and normal. Koletsky designated the strain of rats as Obese SHR and sent some animals to Hansen at the National Institutes of Health in Bethesda (NIH), who created a defined and stabilized strain. This proved difficult to do due to the extensive load of deleterious genes in the complex background genome. Hansen crossed the Obese SHR with two in-house inbred strains at NIH, the SHR/N and the LA/N, and then backcrossed repeatedly to the parent strains to create (after 12 backcrossings) two congenic strains, the SHR/N-cp and the LA/ N-cp (Hansen, 1983; Greenhouse et al., 1988). These two strains were inbred and retained only the cp gene from the original Obese SHR. At the fifth backcross to the LA/N strain, initial breeding stock was sent from NIH to the University of Alberta, where they were the founding animals of a new closed outbred colony retaining approximately 3% of the genome derived from the Obese SHR. At the seventh backcross to the SHR/N strain, breeding stock was sent to the G.D.Searle Company in Indianapolis, where it became the origin of a colony now designated as SHHF/Mcc. These two non-congenic strains, however, both exhibited pathophysiological characteristics not evident in the two related congenic strains. Most importantly, whereas the JCR: LA-cp rats developed atherosclerosis and ischemic myocardial lesions, the SHHF/Mcc rats developed a fatal cardiomyopathy, apparently due to a single gene. The SHHF/Mcc strain has been inbred by McCune for the myocardiopathic trait and now exhibits a very high frequency of cardiomyopathy with ultimate congestive heart failure (Haas et al., 1995).
