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

• Applicant: Professor Andreas Eckhard Kulozik, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2002 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5373186

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.

• DFG Programme: Research Grants