Clinical variability of beta-thalassemia: quality control of gene expression by nonsense mediated decay

无义突变和移码突变导致的提前翻译终止密码子(PTC)是遗传性疾病的常见原因，常见于？地中海贫血。带有这种突变的mRNAs的降解(“无意义介导的衰退”；NMD)减少了C末端截短的、无用的或有害的多肽的数量。B-地中海贫血是第一种有文献记载的具有NMD医学显著影响的遗传疾病，该疾病保护杂合子携带者免受无功能珠蛋白链所造成的显性负面影响的后遗症。NMD在系统发育上是高度保守的，这表明该机制作为基因表达质量控制的途径具有普遍功能。在我们以前结果的基础上，我们开发了一个模型，称为终止后监视模型，用于哺乳动物NMD的机制，该模型假设了两个信号来识别和降解PTC突变的mRNAs：(1)核内，剪接依赖的标记外显子-内含子边界的下游承诺因子(DCF)和(2)细胞质，翻译依赖的识别DCFs相对于翻译终止密码子的位置。我们现在计划测试终止后监测模型的核和细胞质成分，并将在体内分析NMD的生理学相关性。综上所述，我们的目标是对NMD作为一种具有深远医学意义的机制有一个基本的理解。

Premature translation termination codons (PTC) resulting from nonsense and frameshift mutations are common causes of genetic disorders and are frequently found in ß-thalassemia. The degradation of mRNAs with such mutations ("nonsense-mediated decay"; NMD) reduces the amount of C-terminally truncated, useless or harmful polypeptides. ß-thalassemia is the first genetic disorder with a documented medically significant effect of NMD that protects heterozygous carriers from the sequelae of dominant negative effects exerted by non-functional globin chains. NMD is phylogenetically highly conserved suggesting a general function of this mechanism as a pathway for the quality control of gene expression. On the basis of our previous results we developed a model, termed the post-termination surveillance model, for the mechanism of mammalian NMD that postulates two signals for the identification and degradation of PTC-mutated mRNAs: (1) intranuclear, splicing-dependent marking of the exon-intron boundaries with a downstream commitment factor (DCF) and (2) cytoplasmic, translation dependent recognition of the position of the DCFs relative to the translation stop codon. We now plan to test the nuclear and cytoplasmic components of the post-termination surveillance model and will analyze the physiologic relevance of NMD in vivo. Taken together, we aim at a basic understanding of NMD as a mechanism with far reaching medical implications.