Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex
Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex
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DOI：
10.1002/humu.22007
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发表时间：
2012-03-01
期刊：
影响因子：
3.9
通讯作者：
Nellist, Mark
中科院分区：
文献类型：
--
作者：
Hoogeveen-Westerveld, Marianne;Ekong, Rosemary;Nellist, Mark
结节性硬化症（TSC）是由TSC1或TSC2基因突变引起的常染色体显性遗传病。TSC1和TSC2基因产物TSC1和TSC2形成一个复合物，抑制哺乳动物雷帕霉素靶蛋白（mTOR）复合物1 （TORC1）。之前，我们证明了TSC1 n端结构域的致病性氨基酸取代（氨基酸50224）是不稳定的。在这里，我们研究了另外21个未分类的TSC1变体。我们的功能评估发现，氨基酸50和224之间的四个取代（p.L61R, p.G132D, p.F158S和p.R204P）降低了TSC1的稳定性，并阻止了TSC1- tsc2依赖性对TORC1的抑制。在4例（20%）中，我们的功能评估与SIFT氨基酸取代分析软件的预测不一致。我们的新数据证实了我们之前的发现，即TSC1的n端区域对TSC1的功能至关重要。[j] .植物学报，2012,33:476479。(C) 2011 Wiley期刊公司
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Previously, we demonstrated that pathogenic amino acid substitutions in the N-terminal domain of TSC1 (amino acids 50224) are destabilizing. Here we investigate an additional 21 unclassified TSC1 variants. Our functional assessment identified four substitutions (p.L61R, p.G132D, p.F158S, and p.R204P) between amino acids 50 and 224 that reduced TSC1 stability and prevented the TSC1-TSC2-dependent inhibition of TORC1. In four cases (20%), our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our new data confirm our previous finding that the N-terminal region of TSC1 is essential for TSC1 function. Hum Mutat 33:476479, 2012. (C) 2011 Wiley Periodicals, Inc.