Malignant hyperthermia (MH) causes neurological, liver, and kidney damage and death in humans and major economic losses in the swine industry. A single point mutation in the porcine gene for the skeletal muscle ryanodine receptor (ryr1) was found to be correlated with MH in five major breeds of lean, heavily muscled swine. Haplotyping suggests that the mutation in all five breeds has a common origin. Assuming that this is the causal mutation for MH, the development of a noninvasive diagnostic test will provide the basis for elimination of the MH gene or its controlled inclusion in swine breeding programs.

Recent studies have shown that intracellular Ca2' handling is abnormal in the myocardium of patients with end-stage heart failure. Muscles from the failing hearts showed a prolonged Ca2' transient and a diminished capacity to restore a low resting Ca2' level during diastole. Accordingly, we examined whether this defect in Ca2+ transport function is due to alterations in sarcoplasmic reticulum gene expression. We determined the messenger RNA (mRNA) levels of sarcoplasmic reticulum Ca21 transport proteins in failing human hearts from 17 cardiac transplant recipients with a diagnosis of dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The expression levels of each mRNA were compared with each other and then correlated with that of atrial natriuretic factor (ANF) mRNA in the failing ventricle. The mRNA levels for the calcium release channel (ryanodine receptor, RYR2), Ca2' uptake pump (Ca2+-ATPase, SERCA2 isoform), and phospholamban differed significantly between heart samples but showed an inverse relation with that of ventricular ANF mRNA. In contrast, calsequestrin mRNA levels remained unchanged in these failing hearts. In addition, f-myosin and a-cardiac actin mRNA levels also showed an inverse relation with ANF mRNA levels. These changes were observed in both right and left ventricles of hearts with congestive heart failure due to dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The results are consistent with the hypothesis that abnormal calcium handling in the sarcoplasmic reticulum of failing hearts is due to the altered expression of the genes encoding sarcoplasmic reticulum proteins. (Circulation Research 1993;72:463-469) KEY WoRDs * ryanodine receptor * phospholamban * calsequestrin * sarcoplasmic reticulum * Ca2'-ATPase H eart failure is a low cardiac output syndrome characterized by both systolic and diastolic dysfunction. The velocity and extent of ventricular contraction and the rate of pressure development are decreased in heart failure.1-3 The left ventricular (LV) relaxation rates, assessed by maximum rates of LV pressure decline, and the mean velocity of circumferential fiber length shortening in early diastole are also decreased, suggesting an impairment of early diastolic LV relaxation.4 The contraction and relaxation of cardiocytes are regulated by intracellular calcium (Ca'+) concentrations, which, in turn, are controlled

Central core disease (CCD) is a morphologically distinct, autosomal dominant myopathy with variable clinical features. A close association with malignant hyperthermia (MH) has been identified. Since MH and CCD genes have been linked to the skeletal muscle ryanodine receptor (RYR1) gene, cDNA sequence analysis was used to search for a causal RYR1 mutation in a CCD individual. The only amino acid substitution found was an Arg2434His mutation, resulting from the substitution of A for G7301. This mutation was linked to CCD with a lod score of 4.8 at a recombinant fraction of 0.0 in 16 informative meioses in a 130 member family, suggesting a causal relationship to CCD.

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