Pathological Mutations in 5’ Untranslated Regions of Human Genes Sangeeta Chatterjee, Cell and Molecular Biology Laboratory, Department of Biotechnology, University of Pune, Pune, India Sunil Kumar Berwal, Cell and Molecular Biology Laboratory, Department of Biotechnology, University of Pune, Pune, India Jayanta K Pal, Cell and Molecular Biology Laboratory, Department of Biotechnology, University of Pune, Pune, India The 5’ untranslated region (5’-UTR) of a messenger ribo- nucleic acid (mRNA) plays a critical role in translation regulation by influencing mRNA stability and translation efficiency. Functional elements in the 5’-UTR such as internal ribosome entry site (IRES), upstream open read- ing frames (uORFs) and iron responsive element (IRE) serve to fine tune protein expression in response to cel- lular requirement. Genetic variations such as mutations and single nucleotide polymorphisms (SNPs) in the 5’-UTR are associated with a number of human diseases and increased susceptibility to diseases. Such pathological variations disrupt the motifs at the 5’-UTR and cause dis- eases such as X-linked Charcot-Marie-Tooth (CMTX) dis- ease, multiple myeloma, hereditary hyperferritinaemia/ cataract syndrome (HHCS), familial predisposition to melanoma, Marie Unna hereditary hypotrichosis (MUHH), oesophageal cancer and many others. Genetic and molecular profiling of many diseases has shown that a holistic approach of including the UTRs in regular diag- nostic deoxyribonucleic acid (DNA) screening would aid in better disease profiling and disease management. Introduction The messenger ribonucleic acid (mRNA), through its sequence and structure, is capable of regulating its protein output with the help of trans-acting factors. The untranslated regions (UTRs) located at the 5’- and 3’ end of the mRNA play a critical role in this control by influencing mRNA sta- bility, localisation and translation rate. The 5’-UTR of an mRNA harbours features such as internal ribosome entry site (IRES), upstream open reading frames (uORFs) and iron responsive element (IRE) through which such control is exerted (Figure 1). Mutations or polymorphisms in these motifs are capable of causing detrimental effect on human health by defying this ordered control. Mutations, the permanent heritable changes, can be neutral, beneficial or deleterious. Polymorphisms in deoxyribonucleic acid (DNA) sequences are common in human population and are generally neutral in effect. However, single nucleotide polymorphisms (SNPs) can influence disease susceptibility and individual’s response to drugs, vaccines and environ- mental factors. We discuss here such genetic variations affecting the 5’-UTR and their association with diseases, which is summarised in Figure 2. See also: mRNA Untranslated Regions (UTRs); Pathological Variations in 3’- Untranslated Regions of Human Genes Mutations Affecting Internal Ribosome Entry Site Function Internal initiation is an alternative mechanism of translation initiation independent of the cap-mediated ribosomal scan- ning of mRNA. This initiation takes place at IRES, a com- plex secondary structure usually positioned near the AUG in an mRNA. The diversity in length, secondary and tertiary structures, sequence of IRESs and requirement of trans- acting factors for initiation suggest that they may have Advanced article Article Contents . Introduction . Mutations Affecting Internal Ribosome Entry Site Function . Mutations Affecting Iron Responsive Element Function . Mutations Affecting Upstream Open Reading Frame Function . Mutations Affecting the Length of the 5’-UTR and Its Function . Single Nucleotide Polymorphisms in the 5’-UTR . Conclusion Online posting date: 15 th September 2010 ELS subject area: Genetics and Disease How to cite: Chatterjee, Sangeeta; Berwal, Sunil Kumar; and Pal, Jayanta K (September 2010) Pathological Mutations in 5’ Untranslated Regions of Human Genes. In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0022408 ENCYCLOPEDIA OF LIFE SCIENCES & 2010, John Wiley & Sons, Ltd. www.els.net 1