The last step in the cholesterol biosynthesis pathway is conversion of 7-dehydrocholesterol (7-DHC) to cholesterol, catalyzed by a single enzyme, 7-dehyrocholesterol reductase (DHCR7). To date, >150 DHCR7 loss-of-function mutations have been identified, with >1% heterozygous carriers in the human population. Heterozygous carriers have elevated 7-DHC levels. It has been well documented that 7-DHC is toxic, and its numerous spontaneous oxidative products (oxysterols) have disruptive effects on normal cell division and differentiation. 7-DHC levels can also markedly increase as a result of drug treatment. We recently performed a high throughput drug screening and found that aripiprazole (ARI- an atypical antipsychotic) and trazodone (TRZ - an antidepressant) both strongly increased 7-DHC levels. Further literature review revealed that ARI- and TRZ-treated patients have elevated 7-DHC levels, misclassifying some them as SLOS patients - even when they had two intact copies of the Dchr7 gene. In a follow-up experiments we observed that peripheral dermal fibroblasts from human DHCR7+/- mutation carriers also had elevated 7-DHC levels at baseline, which worsened as a result of ARI exposure. Our newest data indicate that ARI treatment of pregnant Dhcr7+/- mice have deleterious effects on the development of the offspring. Based on these data, we hypothesize that ARI/TRZ exposure and DHCR7+/- mutations potentiate each other, elevating 7-DHC levels into a pathological range. As a result, the spontaneous, toxic metabolites of 7-DHC will alter neural development and/or brain function, especially when DHCR7+/- mutation carrier mothers have DHCR7+/- offspring exposed to ARI or TRZ. We will test this central hypothesis in a patient-derived fibroblast model (Aim 1) and neurodevelopmental transgenic mouse models (Aims 2-3) at two different time points using a maternal genotype*offspring genotype*treatment paradigm. Aripiprazole, marketed under the name of Ablilify is the most prescribed drug in the US, and the possibility that heterocyclic cationic amphiphile exposure might be deleterious to >1% of the human DHCR7+/- mutation carriers warrants further investigation. Developing personalized medicine approaches requires understanding Gene*Treatment interactions, and knowing the interaction between maternal genotype*offspring genotype*treatment is necessary to precisely define the population that is potentially vulnerable to ARI/TRZ exposure.
This project will test the vulnerability of the DHCR7+/- gene mutation carriers to aripiprazole (an atypical antipsychotic) and trazodone (an antidepressant) exposure. We will test biochemical, gene expression and behavioral consequences of the interaction between the DHCR7+/- gene mutation and treatment, assessing the long-lasting effects on the progeny.
|Korade, Zeljka; Genaro-Mattos, Thiago C; Tallman, Keri A et al. (2017) Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone exposure. J Lipid Res 58:2139-2146|