Disruption of cholesterol 7α-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation

Shun Ishibashi, Margrit Schwarz, Philip K. Frykman, Joachim Herz, David W. Russell

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194 Scopus citations


Mice deficient in cholesterol 7α-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., Bjorkhem, I., Herz, J., and Russell, D. W. (1996) J. Biol. Chem. 271, 18024-18031). We conclude that cholesterol 7α-hydroxylase is an essential enzyme for normal postnatal development.

Original languageEnglish (US)
Pages (from-to)18017-18023
Number of pages7
JournalJournal of Biological Chemistry
Issue number30
StatePublished - 1996

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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