title: Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review.
abstract: Mendelian diseases contain important biological information regarding developmental effects of gene mutations that can guide drug discovery and toxicity efforts. In this review, we focus on Smith-Lemli-Opitz syndrome (SLOS), a rare Mendelian disease characterized by compound heterozygous mutations in 7-dehydrocholesterol reductase (DHCR7) resulting in severe fetal deformities. We present a compilation of SLOS-inducing DHCR7 mutations and the geographic distribution of those mutations in healthy and diseased populations. We observed that several mutations thought to be disease causing occur in healthy populations, indicating an incomplete understanding of the condition and highlighting new research opportunities. We describe the functional environment around DHCR7, including pharmacological DHCR7 inhibitors and cholesterol and vitamin D synthesis. Using PubMed, we investigated the fetal outcomes following prenatal exposure to DHCR7 modulators. First-trimester exposure to DHCR7 inhibitors resulted in outcomes similar to those of known teratogens (50 vs 48% born-healthy). DHCR7 activity should be considered during drug development and prenatal toxicity assessment.
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, NY, USA.|Observational Health Data Sciences and Informatics, Columbia University, New York, NY, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Boland
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, NY, USA.|Observational Health Data Sciences and Informatics, Columbia University, New York, NY, USA.|Department of Systems Biology, Columbia University, New York, NY, USA.|Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: N P
authors.initials: NP
authors.lastname: Tatonetti
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D019143:Evolution, Molecular; D005260:Female; D005787:Gene Frequency; D040961:Genetic Drift; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D018811:Maternal Exposure / Q000009:adverse effects*; D009154:Mutation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D010641:Phenotype; D011247:Pregnancy; D018570:Risk Assessment; D012307:Risk Factors; D019082:Smith-Lemli-Opitz Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D014807:Vitamin D / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D014807:Vitamin D; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase