Heat-Labile Enzymes in Skin Fibroblasts from Subjects with Progeria

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Abstract
To characterize further the genetic basis of progeria, thermolability studies were performed on three genetically distinct enzymes in crude extracts of cultured skin fibroblasts derived from two subjects with that syndrome. At early passage the progeric fibroblasts, as compared to controls, contained a significantly higher percentage of heat-labile glucose-6-phosphate dehydrogenase (12.83 ± 1.72 vs. 1.11 ± 0.44 [mean ±S.E.M.], p < 0.001), 6-phosphogluconate dehydrogenase (9.71 ± 0.68 vs. 0.67 ± 0.22, p < 0.001), and hypoxanthine-guanine phosphoribosyltransferase (31.40 ± 1.89 vs. 7.67 ±1.71, p < 0.001), and the differences were maintained throughout the in vitro life-span. These data, in conjunction with previous reports of defective HL-A antigens, indicate a widespread defect in genetic expression. The most likely cause appears to be an aberration in protein synthesis or degradation, or both, although multiple somatic mutations cannot be ruled out. Increased thermolability of enzymes in cultured cells may provide a screening test for persons predisposed to progeria and other disorders of premature aging. (N Engl J Med 292:1305–1309, 1975)