Pathological Variations in 3′‐untranslated Regions of Human Genes

The 3¢-untranslated regions (UTRs) of messenger ribonucleic acids (mRNAs) play a critical role in the stabilization, localization and translation of mRNAs. Mutations that disrupt functional elements of the 3¢-UTR of mRNAs such as polyadenylation signal, micro RNA (miRNA) target sites and AU-rich elements lead to production of nonfunctional proteins or reduced amounts of functional proteins. Genetic variations in the 3¢-UTR are associated with disease risk or diseases such as spinocerebellar ataxia 8, Parkinson disease, breast cancer, atopic dermatitis, papillary thyroid carcinoma and many others. With the advent of genetic counselling and promise of personalized medicine, genetic variation in this region of mRNAs is the focus of intense research. Current research shows that this region is of immense significance in the context of translational research.

Key concepts:

  • 3¢-Untranslated regions (UTRs) are noncoding regions of mRNAs.
  • The 3¢-UTR is delimited by stop codon (UAA or UAG or UGA) at the 5¢ end and poly (A) tail at the 3¢ end.
  • Motifs like AU-rich elements, polyadenylation signal, iron responsive elements and others are involved in mRNA stability, localization and translation.
  • Mutations are changes in the DNA/gene of an organism which are heritable.
  • Mutations in the AU-rich elements lead to atypical stabilization of mRNA and associated diseases.
  • Mutations that lead to abolition of canonical polyadenylation signal interfere with efficient transcription termination and polyadenylation of mRNA.
  • Mutations in the 3¢-UTR may alter the binding sites of interacting miRNAs or proteins resulting in deregulation of mRNA translation.
  • Single nucleotide polymorphisms (SNPs) in the 3¢-UTR are associated with individual's drug response and disease risk.

Keywords: 3¢-untranslated regions of mRNA; human diseases; polyadenylation signal; mRNA stability; secondary structure; miRNA target site

Figure 1. Schematic representation of the 3¢-UTR of an eukaryotic mRNA showing its structural features and possible sites of disease-associated mutations. Numericals 1–7 associated with lightening sign denote mutations affecting different regions in the 3¢-UTR of an mRNA. SECIS, Sec insertion sequence; SRE, Sec redefinition element and SNP, single nucleotide polymorphism.
Figure 2. Involvement of various changes in the regulatory elements in the 3¢-UTRs of mRNAs in human diseases.
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Pal, Jayanta K, Chatterjee, Sangeeta, and Berwal, Sunil Kumar(Mar 2010) Pathological Variations in 3′‐untranslated Regions of Human Genes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022450]