Pathological Mutations in 5′ Untranslated Regions of Human Genes

Abstract

Abstract The 5′ untranslated region (5′‐UTR) of a messenger ribonucleic 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 reading frames (uORFs) and iron responsive element (IRE) serve to fine tune protein expression in response to cellular 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 diseases such as X‐linked Charcot‐Marie‐Tooth (CMTX) disease, 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 diagnostic deoxyribonucleic acid (DNA) screening would aid in better disease profiling and disease management. Key Concepts: 5′ Untranslated regions (UTRs) are noncoding regions of messenger RNAs (mRNAs). The 5′‐UTR is delimited by transcription initiation site at 5′ end and the physiological start codon (AUG) at the 3′ end. Motifs such as internal ribosome entry site (IRES), upstream open reading frames (uORFs), iron responsive element (IRE) and others are involved in mRNA stability and translation control. mRNAs encoding regulatory proteins need to be strongly and precisely regulated. These mRNAs are often endowed with longer than average 5′‐UTR, uORFs and stable secondary structures that regulate their translation efficiency. Mutations are changes in the DNA/genes of an organism which are heritable. Mutations that disrupt the functional elements of the 5′‐UTR are often associated with diseases. Single nucleotide polymorphisms (SNPs) in the 5′‐UTR are associated with individual's drug response and disease risk.