Pathological Mutations in 5′ Untranslated Regions of Human Genes

Abstract

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.

Keywords: 5′ untranslated regions of mRNA; human diseases; truncations; upstream open‐reading frames (uORFs); internal ribosome entry site (IRES); iron‐responsive element (IRE)

Figure 1. Schematic representation of the 5′‐UTR of a eukaryotic mRNA showing its structural features and possible sites of disease‐associated mutations. Numbers 1–5 associated with lightening signs denote mutations affecting different regions in the 5′‐UTR of an mRNA. Upstream open‐reading frames, uORFs; internal ribosome entry site, IRES; iron‐responsive element, IRE and single nucleotide polymorphisms, SNPs.
Figure 2. Involvement of various changes in the regulatory elements in the 5′‐UTRs of mRNAs in human diseases.
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Chatterjee, Sangeeta, Rao, Shilpa J, and Pal, Jayanta K(Oct 2017) Pathological Mutations in 5′ Untranslated Regions of Human Genes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022408.pub2]