title: Disruption of cholesterol 7alpha-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation.
abstract: Mice deficient in cholesterol 7alpha-hydroxylase, the rate-limiting enzyme of bile acid biosynthesis, were constructed by targeted disruption of the Cyp7 gene. The introduced mutation removed exons 3-5 of the gene and gave rise to a null allele that encoded no immunoreactive or enzymatically active protein. Heterozygous carriers of the disrupted gene (Cyp7+/-) were phenotypically normal. Homozygous animals (Cyp7-/-) appeared normal at birth, but died within the first 18 days of life. Approximately 40% of the animals died between postnatal days 1 and 4 and 45% between days 11 and 18. The addition of vitamins to the water of nursing mothers prevented deaths in the early period, whereas the addition of cholic acid to chow prevented deaths in the later period. Newborn Cyp7-/- mice whose mothers were maintained on unsupplemented chow failed to gain weight at a normal rate and developed oily coats, hyperkeratosis, and apparent vision defects. These symptoms waned at 3 weeks of life, and their disappearance was accompanied by a marked increase in survival. In the accompanying study, the induction of an alternate pathway of bile acid biosynthesis is shown to underlie this unusual time course (Schwarz, M., Lund, E. G., Setchell, K. D. R., Kayden, H. J., Zerwekh, J. E., Björkhem, I., Herz, J., and Russell, D. W. (1996) J. Biol. Chem. 271, 18024-18031). We conclude that cholesterol 7alpha-hydroxylase is an essential enzyme for normal postnatal development.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9046, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ishibashi
authors.forename: M
authors.initials: M
authors.lastname: Schwarz
authors.forename: P K
authors.initials: PK
authors.lastname: Frykman
authors.forename: J
authors.initials: J
authors.lastname: Herz
authors.forename: D W
authors.initials: DW
authors.lastname: Russell
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002790:Cholesterol 7-alpha-Hydroxylase / Q000172:deficiency* / Q000235:genetics; D019826:Cholic Acid; D002793:Cholic Acids / Q000096:biosynthesis / Q000494:pharmacology*; D004032:Diet; D005804:Genes, Lethal; D006720:Homozygote; D051379:Mice; D008817:Mice, Mutant Strains; D008861:Microsomes / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010641:Phenotype; D012867:Skin / Q000473:pathology; D014815:Vitamins / Q000494:pharmacology*; D015430:Weight Gain
chemical_list: D002793:Cholic Acids; D014815:Vitamins; D002790:Cholesterol 7-alpha-Hydroxylase; D019826:Cholic Acid