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

由无义突变和移码突变引起的过早翻译终止密码子（PTC）是遗传性疾病的常见原因，并且经常在β-地中海贫血中发现。具有这种突变的mRNA的降解（“无义介导的衰变”; NMD）减少了C末端截短的、无用的或有害的多肽的量。β-地中海贫血是第一种具有记录在案的NMD医学显著效应的遗传性疾病，其保护杂合携带者免受由非功能性珠蛋白链施加的显性负效应的后遗症。NMD在遗传学上是高度保守的，这表明该机制作为基因表达质量控制途径的一般功能。基于我们以前的结果，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，该模型假定用于鉴定和降解PTC突变mRNA的两个信号：（1）具有下游承诺因子（DCF）的外显子-内含子边界的核内剪接依赖性标记，和（2）细胞质，DCF相对于翻译终止密码子的位置的翻译依赖性识别。我们现在计划测试细胞核和细胞质成分的终止后监测模型，并将在体内分析NMD的生理相关性。总之，我们的目标是对NMD作为一种具有深远医学影响的机制有一个基本的了解。

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.