A Novel Mutation of the DHCR7 Gene in a Sicilian Compound Heterozygote with Smith-Lemli-Opitz Syndrome

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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Computational Investigation of the Missense Mutations in DHCR7 Gene Associated with Smith-Lemli-Opitz Syndrome

Peng

Myers

Wenxing

et al. 2018

IJMS

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Smith-Lemli-Opitz syndrome (SLOS) is a cholesterol synthesis disorder characterized by physical, mental, and behavioral symptoms. It is caused by mutations in 7-dehydroxycholesterolreductase gene (DHCR7) encoding DHCR7 protein, which is the rate-limiting enzyme in the cholesterol synthesis pathway. Here we demonstrate that pathogenic mutations in DHCR7 protein are located either within the transmembrane region or are near the ligand-binding site, and are highly conserved among species. In contrast, non-pathogenic mutations observed in the general population are located outside the transmembrane region and have different effects on the conformational dynamics of DHCR7. All together, these observations suggest that the non-classified mutation R228Q is pathogenic. Our analyses indicate that pathogenic effects may affect protein stability and dynamics and alter the binding affinity and flexibility of the binding site.

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A Novel Mutation of the DHCR7 Gene in a Sicilian Compound Heterozygote with Smith-Lemli-Opitz Syndrome

Abstract: The present study describes a Sicilian patient, a carrier of a novel mutation of the DHCR7 gene (I251N), which is responsible in a compound heterozygous state for a severe form of SLOS.

Cited by 3 publications

References 19 publications

Pregnancy and life after preimplantation genetic diagnosis of Smith-Lemli-Opitz syndrome

Pregnancy and life after preimplantation genetic diagnosis of Smith-Lemli-Opitz syndrome

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

Computational Investigation of the Missense Mutations in DHCR7 Gene Associated with Smith-Lemli-Opitz Syndrome

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