Tuberous sclerosis complex
Tuberous sclerosis complex
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DOI：
10.1038/nrdp.2016.35
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发表时间：
2016-05-26
影响因子：
81.5
通讯作者：
Thiele, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Henske, Elizabeth P.;Jozwiak, Sergiusz;Thiele, Elizabeth A.
多发性硬化症（TSC）是一种常染色体显性遗传疾病，影响多个器官系统，由两个基因之一的功能丧失突变引起：TSC 1或TSC 2。这种疾病可以影响成人和儿童。Bourneville于1880年首次深入描述，现在估计全世界有近200万人受到这种疾病的影响。TSC的临床特征是独特的，个体之间甚至在一个家庭内可能差异很大。该疾病的主要特征包括脑、皮肤、心脏、肺和肾的肿瘤，癫痫发作和TSC相关的神经精神障碍，其中可能包括自闭症谱系障碍和认知障碍。TSC 1（也称为hamartin）和TSC 2（也称为tuberin）形成TSC蛋白复合物，其作为雷帕霉素（mTOR）信号传导途径的机制靶点的抑制剂，而mTOR信号传导途径又在调节细胞生长、增殖、自噬以及蛋白质和脂质合成中发挥关键作用。除了全球范围内的几项随机对照试验外，基础和转化研究的显著进展已导致监管机构批准使用mTOR抑制剂治疗肾血管平滑肌脂肪瘤、脑室管膜下巨细胞星形细胞瘤和肺淋巴管平滑肌瘤病，但需要进一步研究以确定治疗性治疗的完整适应症。在本书中，我们回顾了TSC领域的最新知识，包括疾病的分子和细胞基础，医疗管理，主要的知识差距和正在进行的治疗研究。
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure.