Protein synthesis is often regulated at the level of initiation of translation, making it a critical step. This regulation occurs by both the cis-regulatory elements, which are located in the 5 -and 3 -UTRs (untranslated regions), and trans-acting factors. A breakdown in this regulation machinery can perturb cellular metabolism, leading to various physiological abnormalities. The highly structured UTRs, along with features such as GC-richness, upstream open reading frames and internal ribosome entry sites, significantly influence the rate of translation of mRNAs. In this review, we discuss how changes in the cis-regulatory sequences of the UTRs, for example, point mutations and truncations, influence expression of specific genes at the level of translation. Such modifications may tilt the physiological balance from healthy to diseased states, resulting in conditions such as hereditary thrombocythaemia, breast cancer, fragile X syndrome, bipolar affective disorder and Alzheimer's disease. This information tends to establish the crucial role of UTRs, perhaps as much as that of coding sequences, in health and disease.

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.

a b s t r a c tThe human heme-regulated eIF2a kinase, also called the human heme-regulated inhibitor (hHRI) is significantly up-regulated particularly at the level of translation during stress. In this report we show that during lead-stress, the regulation of hHRI mRNA translation is mediated through its 5 0 -untranslated region (UTR) that interacts with specific trans-acting factors. Further, vimentin has been identified as one of the trans-acting factors that contribute to this regulation.

The 5′ untranslated region (5′‐UTR) of a messenger ribonucleic acid (mRNA) plays a critical role in translational 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 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 ribonucleic acids (mRNAs). The 5′‐UTR is delimited by transcriptional 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 translational 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 drug response and disease risk in an individual.

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