Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone treatment

胆固醇生物合成途径的最后一步是将7-脱氢胆固醇(7-DHC)转化为 胆固醇，由一种单一的酶，7-脱氢胆固醇还原酶(DHCR7)催化。到目前为止，&gt；150 DHCR7 功能缺失突变已被鉴定，在人类人群中有1%的杂合携带者。 杂合子携带者7-DHC水平升高。已经有充分的文件证明7-DHC是有毒的，它的 大量的自发氧化产物(氧化甾醇)对正常的细胞分裂和 差异化。7-DHC水平也会因药物治疗而显著升高。我们最近表演了 高通量药物筛选发现阿立哌唑(ARI-非典型抗精神病药物)和曲唑酮 (TRZ-一种抗抑郁药)两者都显著增加了7-DHC的水平。进一步的文献综述显示，ARI- 接受TRZ治疗的患者7-DHC水平升高，甚至将一些患者错误地归类为SLOS患者 当他们有两个完整的Dchr7基因拷贝时。在后续实验中，我们观察到外周血细胞 来自人DHCR7+/-突变携带者的真皮成纤维细胞在基线时也有升高的7-DHC水平，这 由于急性呼吸窘迫综合征的暴露而恶化。我们的最新数据表明ARI对怀孕的Dhcr7+/-小鼠的治疗 对后代的发育有有害的影响。根据这些数据，我们假设 ARI/TRZ暴露和DHCR7+/-突变相互增强，使7-DHC水平上升到 病理范围。因此，7-DHC的自发毒性代谢产物将改变神经。 发育和/或脑功能，特别是当dhr7+/-突变携带者母亲患有dhr7+/-时 暴露于ARI或TRZ的后代。我们将在患者来源的成纤维细胞模型中检验这一中心假设 (目标1)和神经发育转基因小鼠模型(目标2-3)在两个不同的时间点使用 母系基因*子代基因*治疗范式。阿立哌唑，以Ablilify® 是美国最常见的处方药，杂环阳离子两亲性接触的可能性可能 对人体有害1%的人DHCR7+/-突变携带者值得进一步研究。发展中 个性化医疗方法需要了解基因*治疗的相互作用，并了解 母体基因和子代基因之间的相互作用的处理是精确定义 潜在易受ARI/TRZ暴露的人群。

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.