title: 3-Hydroxy-3-methylglutaryl-CoA lyase (HL): gene targeting causes prenatal lethality in HL-deficient mice.
abstract: 3-Hydroxy-3-methylglutaryl-CoA lyase (HL, EC 4.1.3.4) catalyses the last step 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, we created a strain of HL-deficient mice. Heterozygous HL-deficient mice are clinically normal and fibroblasts from homozygous HL-deficient embryos grow normally despite absence of HL activity. In contrast, homozygous HL-deficient embryos die at approximately 11.5 days post-coitum. Histologically, HL-deficient embryos show marked vacuolization, particularly in liver. Ultrastructural studies of hepatocytes obtained before death from HL-deficient embryos reveal abnormal dilated mitochondria. HL-deficient mice are the first mammalian example of a disease primarily affecting CoA ester metabolism with abnormal prenatal development.
authors.affiliation: Service de Génétique Médicale and Département de Pathologie, Hôpital Sainte-Justine, 3175 Cote Ste-Catherine, Montréal H3T 1C5, Québec, Canada.
authors.forename: S P
authors.initials: SP
authors.lastname: Wang
authors.forename: J D
authors.initials: JD
authors.lastname: Marth
authors.forename: L L
authors.initials: LL
authors.lastname: Oligny
authors.forename: M
authors.initials: M
authors.lastname: Vachon
authors.forename: M F
authors.initials: MF
authors.lastname: Robert
authors.forename: L
authors.initials: L
authors.lastname: Ashmarina
authors.forename: G A
authors.initials: GA
authors.lastname: Mitchell
mesh_terms: D000483:Alleles; D000818:Animals; D001947:Breeding; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000166:cytology / Q000201:enzymology; D005314:Embryonic and Fetal Development / Q000235:genetics; D005260:Female; D005313:Fetal Death / Q000201:enzymology / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D018390:Gene Targeting; D006579:Heterozygote; D006720:Homozygote; D008099:Liver / Q000196:embryology / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D007652:Oxo-Acid-Lyases / Q000172:deficiency / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D007652:Oxo-Acid-Lyases; C021410:3-hydroxy-3-methylglutaryl-coenzyme A lyase