3-hydroxy-3-methylglutaryl-CoA lyase (HL): gene targeting causes prenatal lethality in HL-deficient mice

3-Hydroxy-3-methylglutaryl-CoA lyase (HL, EC 4.1.3.4) catalyses the last st ep of ketogenesis from leucine and fatty acids. HL deficiency in humans is one of the many inborn errors of CoA ester metabolism. By gene targeting, w e created a strain of HL-deficient mice. Heterozygous HL-deficient mice are clinically normal and fibroblasts from homozygous HL-deficient embryos gro w normally despite absence of HL activity. In contrast, homozygous HL-defic ient embryos die at similar to 11.5 days post-coitum. Histologically, HL-de ficient embryos show marked vacuolization, particularly in liver. Ultrastru ctural studies of hepatocytes obtained before death from HL-deficient embry os reveal abnormal dilated mitochondria. HL-deficient mice are the first ma mmalian example of a disease primarily affecting CoA ester metabolism with abnormal prenatal development.