title: Mouse knockout of the cholesterogenic cytochrome P450 lanosterol 14alpha-demethylase (Cyp51) resembles Antley-Bixler syndrome.
abstract: Antley-Bixler syndrome (ABS) represents a group of heterogeneous disorders characterized by skeletal, cardiac, and urogenital abnormalities that have frequently been associated with mutations in fibroblast growth factor receptor 2 or cytochrome P450 reductase genes. In some ABS patients, reduced activity of the cholesterogenic cytochrome P450 CYP51A1, an ortholog of the mouse CYP51, and accumulation of lanosterol and 24,25-dihydrolanosterol has been reported, but the role of CYP51A1 in the ABS etiology has remained obscure. To test whether Cyp51 could be involved in generating an ABS-like phenotype, a mouse knock-out model was developed that exhibited several prenatal ABS-like features leading to lethality at embryonic day 15. Cyp51(-/-) mice had no functional Cyp51 mRNA and no immunodetectable CYP51 protein. The two CYP51 enzyme substrates (lanosterol and 24,25-dihydrolanosterol) were markedly accumulated. Cholesterol precursors downstream of the CYP51 enzymatic step were not detected, indicating that the targeting in this study blocked de novo cholesterol synthesis. This was reflected in the up-regulation of 10 cholesterol synthesis genes, with the exception of 7-dehydrocholesterol reductase. Lethality was ascribed to heart failure due to hypoplasia, ventricle septum, and epicardial and vasculogenesis defects, suggesting that Cyp51 deficiency was involved in heart development and coronary vessel formation. As the most likely downstream molecular mechanisms, alterations were identified in the sonic hedgehog and retinoic acid signaling pathways. Cyp51 knock-out mice provide evidence that Cyp51 is essential for embryogenesis and present a potential animal model for studying ABS syndrome in humans.
authors.affiliation: Department of Animal Science, Biotechnical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Rok
authors.initials: R
authors.lastname: Keber
authors.affiliation: Department of Animal Science, Biotechnical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia; Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia.
authors.forename: Helena
authors.initials: H
authors.lastname: Motaln
authors.affiliation: INSERM U907, Parc Valrose, Nice, France; Université de Nice, Sophia-Antipolis, Parc Valrose, Nice, France.
authors.forename: Kay D
authors.initials: KD
authors.lastname: Wagner
authors.affiliation: Institute of Biochemistry, Centre for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Debeljak
authors.affiliation: Université de Nice, Sophia-Antipolis, Parc Valrose, Nice, France; Centre de Biochimie, INSERM U636, Parc Valrose, Nice, France.
authors.forename: Minoo
authors.initials: M
authors.lastname: Rassoulzadegan
authors.affiliation: Institute of Biochemistry, Centre for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Jure
authors.initials: J
authors.lastname: Ačimovič
authors.affiliation: Institute of Biochemistry, Centre for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
authors.affiliation: Department of Animal Science, Biotechnical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia; National Institute of Chemistry, 1000 Ljubljana, Slovenia and. Electronic address: simon.horvat@bf.uni-lj.si.
authors.forename: Simon
authors.initials: S
authors.lastname: Horvat
mesh_terms: D000818:Animals; D054882:Antley-Bixler Syndrome Phenotype; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000201:enzymology; D047108:Embryonic Development / Q000235:genetics; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007810:Lanosterol / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism; D010496:Pericardium / Q000201:enzymology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058886:Sterol 14-Demethylase / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
chemical_list: C548418:CYP51A1 protein, human; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D007810:Lanosterol; D014212:Tretinoin; C015316:lanostenol; D002784:Cholesterol; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2