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The pharmacogenomics journal
10, 2016;16 (5): 411-29.

Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review.

M R Boland, N P Tatonetti
Author Information
  1. M R Boland: Department of Biomedical Informatics, Columbia University, New York, NY, USA.
  2. N P Tatonetti: Department of Biomedical Informatics, Columbia University, New York, NY, USA.
PMID: 27401223 DOI: 10.1038/tpj.2016.48

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.

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Grants

  1. R01 GM107145/NIGMS NIH HHS
  2. T15 LM007079/NLM NIH HHS
  3. U54 CA209997/NCI NIH HHS

MeSH Term

Abnormalities, Drug-Induced
Animals
Cholesterol
Enzyme Inhibitors
Evolution, Molecular
Female
Gene Frequency
Genetic Drift
Genetic Predisposition to Disease
Heredity
Humans
Maternal Exposure
Mutation
Oxidoreductases Acting on CH-CH Group Donors
Pharmacogenetics
Phenotype
Pregnancy
Risk Assessment
Risk Factors
Smith-Lemli-Opitz Syndrome
Vitamin D

Chemicals

Enzyme Inhibitors
Vitamin D
Cholesterol
Oxidoreductases Acting on CH-CH Group Donors
7-dehydrocholesterol reductase
Journal Article Review Systematic Review
Article has an altmetric score of 5

Word Cloud

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