Justice Monica J, Buchovecky Christie M, Kyle Stephanie M, Djukic Aleksandra
Department of Molecular and Human Genetics; Baylor College of Medicine; Houston, TX USA.
Tri-state Rett Syndrome Clinic; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Bronx, NY USA.
Rare Dis. 2013 Dec 18;1:e27265. doi: 10.4161/rdis.27265. eCollection 2013.
Rett syndrome (RTT), an X-linked neurological disorder caused by mutations in MECP2, may have a metabolic component. We reported a genetic suppressor screen in a Mecp2-null mouse model to identify pathways for therapeutic improvement of RTT symptoms. Of note, one suppressor mutation implied that cholesterol homeostasis was perturbed in Mecp2 null mice; indeed, cholesterol synthesis was elevated in the brain and body system. Remarkably, the genetic effect of downregulating the cholesterol pathway could be mimicked chemically by statin drugs, improving motor symptoms, and increasing longevity in the mouse. Our work linked cholesterol metabolism to RTT pathology for the first time. Both neurological and systemic effects of perturbed cholesterol homeostasis overlap with many RTT symptoms. Here we show in patients that peripheral cholesterol, triglycerides, and/or LDLs may be elevated early in RTT disease onset, providing a biomarker for patients that could be aided by therapeutic interventions that modulate lipid metabolism.
瑞特综合征（RTT）是一种由MECP2基因突变引起的X连锁神经疾病，可能存在代谢成分。我们在Mecp2基因敲除小鼠模型中进行了一项基因抑制筛选，以确定改善RTT症状的治疗途径。值得注意的是，一个抑制突变表明Mecp2基因敲除小鼠的胆固醇稳态受到干扰；事实上，大脑和身体系统中的胆固醇合成增加。值得注意的是，下调胆固醇途径的基因效应可以通过他汀类药物在化学上模拟，改善运动症状，并延长小鼠寿命。我们的工作首次将胆固醇代谢与RTT病理联系起来。胆固醇稳态紊乱的神经和全身效应与许多RTT症状重叠。在这里，我们在患者中发现，外周胆固醇、甘油三酯和/或低密度脂蛋白可能在RTT疾病发作早期升高，为患者提供了一种生物标志物，可通过调节脂质代谢的治疗干预措施得到帮助。
