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 stabilisation, localisation and translation of mRNAs. Mutations that disrupt functional elements of the 3′‐UTR of mRNAs such as polyadenylation signal, microribonucleic acid (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 personalised 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 such as AU‐rich elements, polyadenylation signal, iron responsive elements and others are involved in mRNA stability, localisation and translation.
  • Mutations are changes in the DNA/gene of an organism which are heritable.
  • Mutations in the AU‐rich elements lead to atypical stabilisation 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 region 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. Numerals 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.


Abelson JF, Kwan KY, O'Roak BJ, et al. (2005) Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 310: 317–320.

Adams BD, Furneaux H and White BA (2007) The micro‐ribonucleic acid (miRNA) miR‐206 targets the human estrogen receptor‐alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines. Molecular Endocrinology 21: 1132–1147.

Allamand V, Richard P, Lescure A, et al. (2006) A single homozygous point mutation in a 3′‐untranslated region motif of selenoprotein N mRNA causes SEPN1‐related myopathy. EMBO Reports 7: 450–454.

Amato F, Seia M, Giordano S, et al. (2013) Gene mutation in MicroRNA target sites of CFTR gene: a novel pathogenetic mechanism in cystic fibrosis? PLoS One 8 (3): e60448. DOI: 10.1371/journal.pone.0060448.

Bhattacharya A and Cui Y (2016) SomamiR 2.0: A database of cancer somatic mutations altering microRNA‐ceRNA interactions. Nucleic Acids Research 44 (D1): D1005–D1010.

Beetz C, Schüle R, Deconinck T, et al. (2008) REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain 131: 1078–1086.

Bennett CL, Brunkow ME, Ramsdell F, et al. (2001) A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA→AAUGAA) leads to the IPEX syndrome. Immunogenetics 53: 435–439.

Brewster BL, Rossiello F, French JD, et al. (2012) Identification of fifteen novel germline variants in the BRCA1 3′UTR reveals a variant in a breast cancer case that introduces a functional miR‐103 target site. Human Mutation 33 (12): 1665–1675.

Cardo LF, Coto E, Ribacoba R, et al. (2014) The screening of the 3′UTR sequence of LRRK2 identified an association between the rs66737902 polymorphism and Parkinson's disease. Journal of Human Genetics 59 (6): 346–348. DOI: 10.1038/jhg.2014.26.

Ceolin L, Romitti M, Siqueira DR, et al. (2016) Effect of 3′UTR RET variants on RET mRNA secondary structure and disease presentation in medullary thyroid carcinoma. PLoS One 11 (2): e0147840. DOI: 10.1371/journal.pone.0147840.

Chang CY, Chen Y, Lai MT, et al. (2013) BMPR1B up‐regulation via a miRNA binding site variation defines endometriosis susceptibility and CA125 levels. PLoS One 8 (12): e80630. DOI: 10.1371/journal.pone.0080630.

Chen K, Song F, Calin GA, et al. (2008) Polymorphisms in microRNA targets: a gold mine for molecular epidemiology. Carcinogenesis 29: 1306–1311.

Chien YL, Liu CM, Fann CS, et al. (2009) Association of the 3′ region of COMT with schizophrenia in Taiwan. Journal of the Formosan Medical Association 108: 301–319.

Chin LJ, Ratner E, Leng S, et al. (2008) A SNP in a let‐7 microRNA complementary site in the KRAS 3′ untranslated region increases non‐small cell lung cancer risk. Cancer Research 68: 8535–8540.

Chuzhanova N, Cooper DN, Férec C and Chen JM (2007) Searching for potential microRNA‐binding site mutations amongst known disease‐associated 3′ UTR variants. Genomic Medicine 1: 29–33.

Cleary JD and Ranum LP (2013) Repeat‐associated non‐ATG (RAN) translation in neurological disease. Human Molecular Genetics 22 (R1): R45–R51. DOI: 10.1093/hmg/ddt371.

Curinha A, Oliveira BS, Pereira‐Castro I, et al. (2014) Implications of polyadenylation in health and disease. Nucleus 5 (6): 508–519.

Daughters RS, Tuttle DL, Gao W, et al. (2009) RNA gain‐of‐function in spinocerebellar ataxia type 8. PLoS Genetics 5 (8): e1000600. DOI: 10.1371/journal.pgen.1000600.

Ding L, Jiang Z, Chen Q, et al. (2015) A functional variant at mir‐520a binding site in PIK3CA alters susceptibility to colorectal cancer in a Chinese Han population. BioMed Research International 2015: 373252. DOI: 10.1155/2015/373252.

Delay C, Calon F, Mathews P, et al. (2011) Alzheimer‐specific variants in the 3′UTR of Amyloid precursor protein affect microRNA function. Molecular Neurodegeneration 6: 70. DOI: 10.1186/1750-1326-6-70.

Dusl M, Senderek J, Muller JS, et al. (2015) A 3′‐UTR mutation creates a microRNA target site in the GFPT1 gene of patients with congenital myasthenic syndrome. Human Molecular Genetics 24 (12): 3418–3426.

Egli RJ, Southam L, Wilkins JM, et al. (2009) Functional analysis of the osteoarthritis susceptibility‐associated GDF5 regulatory polymorphism. Arthritis and Rheumatism 60: 2055–2064.

Ghanbari M, Darweesh SKL, de Looper HWJ, et al. (2016) Genetic variants in microRNAs and their binding sites are associated with the risk of Parkinson disease. Human Mutation 37 (3): 292–300.

Goodwin M and Swanson MS (2014) RNA‐binding protein mis‐regulation in microsatellite expansion disorders. Advances in Experimental Medicine and Biology 825: 353–388.

Harteveld CL, Losekoot M, Haak H, Heister GA, et al. (1994) A novel polyadenylation signal mutation in the α2‐globin gene causing α‐thalassaemia. British Journal of Haematology 87: 139–143.

Haas U, Sczakiel G and Laufer SD (2012) MicroRNA‐mediated regulation of gene expression is affected by disease‐associated SNPs within the 3′‐UTR via altered RNA structure. RNA Biology 9 (6): 924–937.

He H, Jazdzewski K, Li W, et al. (2005) The role of microRNA genes in papillary thyroid carcinoma. Proceedings of the National Academy of Sciences of the United States of America 102: 19075–19080.

Higgs DR, Goodbourn SE, Lamb J, et al. (1983) α‐Thalassaemia caused by a polyadenylation signal mutation. Nature 306: 398–400.

Hu Z, Chen J, Tian T, et al. (2008) Genetic variants of miRNA sequences and non‐small cell lung cancer survival. Journal of Clinical Investigation 118: 2600–2608.

Iwanaga E, Nanri T, Mitsuya H and Asou N (2011) Mutation in the RNA binding protein TIS11D/ZFP36L2 is associated with the pathogenesis of acute leukemia. International Journal of Oncology 38 (1): 25–31.

Jakubowska A, Gronwald J, Górski B, et al. (2007) The 3′ untranslated region C>T polymorphism of prohibitin is a breast cancer risk modifier in Polish women carrying a BRCA1 mutation. Breast Cancer Research and Treatment 104: 67–74.

Jensen KP, Covault J, Conner TS, et al. (2009) A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR‐96 and associates with aggressive human behaviors. Molecular Psychiatry 14: 381–389.

Jones AL, Holliday EG, Mowry BJ, et al. (2009) CTLA‐4 single‐nucleotide polymorphisms in a Caucasian population with schizophrenia. Brain, Behavior, and Immunity 23 (3): 347–350.

Kapeller J, Houghton LA, Mönnikes H, et al. (2008) First evidence for an association of a functional variant in the microRNA‐510 target site of the serotonin receptor type 3E gene with diarrhea predominant irritable bowel syndrome. Human Molecular Genetics 17: 2967–2977.

Landi D, Gemignani F, Naccarati A, et al. (2008) Polymorphisms within micro‐RNA‐binding sites and risk of sporadic colorectal cancer. Carcinogenesis 29: 579–584.

Landi D, Moreno V, Guino E, et al. (2011) Polymorphism affecting micro‐RNA regulation and associated with the risk of dietary‐related cancers: a review from the literature and new evidence for a functional role of rs17281995 (CD86) and rs1051690 (INSR), previously associated with colorectal cancer. Mutation Research 7 (17): 109–115.

Latronico MV and Condorelli G (2009) MicroRNAs and cardiac pathology. Nature Reviews. Cardiology 6: 419–429.

López de Silanes I, Quesada MP and Esteller M (2007) Aberrant regulation of messenger RNA 3′‐untranslated region in human cancer. Cellular Oncology 29: 1–17.

Losekoot M, Fodde R, Harteveld CL, et al. (1991) Homozygous beta + thalassaemia owing to a mutation in the cleavage‐polyadenylation sequence of the human beta globin gene. Journal of Medical Genetics 28: 252–255.

Maiti B, Arbogast S, Allamand V, et al. (2009) A mutation in the SEPN1 selenocysteine redefinition element (SRE) reduces selenocysteine incorporation and leads to SEPN1‐related myopathy. Human Mutation 30: 411–416.

Martin MM, Buckenberger JA, Jiang J, et al. (2007) The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microrna‐155 binding. Journal of Biological Chemistry 282: 24262–24269.

Menabo S, Balsamo A, Baldazzi L, et al. (2012) A sequence variation in 3′ utr of cyp21a2 gene correlates with a mild form of congenital adrenal hyperplasia. Journal of Endocrinolical Investigation 35: 298–305.

Mishra PJ and Bertino JR (2009) MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics 10: 399–416.

Moghadaszadeh B, Petit N, Jaillard C, et al. (2001) Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nature Genetics 29: 17–18.

Moseley ML, Zu T, Ya I, et al. (2006) Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nature Genetics 38: 758–769.

Nossent AY, Hansen JL, Doggen C, et al. (2011) SNPs in microRNA binding sites in 3′‐UTRs of RAAS genes influence arterial blood pressure and risk of myocardial infarction. American Journal of Hypertension 24: 999–1006.

Orkin SH, Cheng TC, Antonarakis SE, et al. (1985) Thalassemia due to a mutation in the cleavage‐polyadenylation signal of the human beta‐globin gene. The EMBO Journal 4 (2): 453–456.

Pardini B, Rosa F, Barone E, et al. (2013) Variation within 3′‐UTRs of base excision repair genes and response to therapy in colorectal cancer patients: a potential modulation of microRNAs binding. Clinical Cancer Research 19: 6044–6056. DOI: 10.1158/1078-0432.CCR-13-0314.

Prior JF, Lim E, Lingam N, Raven JL and Finlayson J (2007) A moderately severe α‐thalassemia condition resulting from a combination of the α2 polyadenylation signal (AATAAA → AATA‐‐) mutation and a 3.7 Kb α gene deletion in an Australian family. Hemoglobin 31: 173–177.

Ranum LPW and Cooper TA (2006) RNA‐mediated neuromuscular disorders. Annual Review of Neuroscience 29: 259–277.

Reamon‐Buettner SM, Cho SH and Borlak J (2007) Mutations in the 3′‐untranslated region of GATA4 as molecular hotspots for congenital heart disease (CHD). BMC Medical Genetics 8: 38. DOI: 10.1186/1471-2350-8-38.

Rund D, Dowling C, Najjar K, et al. (1992) Two mutations in the beta‐globin polyadenylylation signal reveal extended transcripts and new RNA polyadenylylation sites. Proceedings of the National Academy of Sciences of the United States of America 89: 4324–4328.

Rukov JL, Wilentik R, Jaffe I, et al. (2014) Pharmaco‐miR:linking microRNAs and drug effects. Briefings in Bioinformatics 15 (4): 648–659.

Sætrom P, Biesinger J, Li SM, et al. (2009) A risk variant in an miR‐125b binding site in BMPR1B is associated with breast cancer pathogenesis. Cancer Research 69: 7459–7465.

Sethupathy P, Borel C, Gagnebin M, et al. (2007) Human microRNA‐155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3′ untranslated region: a mechanism for functional single‐nucleotide polymorphisms related to phenotypes. American Journal of Human Genetics 81: 405–413.

Sethupathy P and Collins FS (2008) MicroRNA target site polymorphisms and human disease. Trends in Genetics 24: 489–497.

Song P, Zhu H, Zhang D, et al. (2014) A genetic variant of miR‐148a binding site in the SCRN1 3′‐UTR is associated with susceptibility and prognosis of gastric cancer. Scientific Reports 4: 7080. DOI: 10.1038/srep07080.

Song P, Wang W, Tao G, et al. (2015) A miR‐29c binding site genetic variant in the 3′‐untranslated region of LAMTOR3 gene is associated with gastric cancer risk. Biomedicine & Pharmacotherapy 69: 70–75.

Sotiriou S, Gibney G, Baxevanis AD, et al. (2009) A single nucleotide polymorphism in the 3′ UTR of the SNCA gene encoding alpha‐synuclein is a new potential susceptibility locus for Parkinson disease. Neuroscience Letters 461: 196–201.

Tan Z, Randall G, Fan J, et al. (2007) Allele‐specific targeting of microRNAs to HLA‐G and risk of asthma. American Journal of Human Genetics 81: 829–834.

Tan C, Liu S, Tan S, et al. (2015) Polymorphisms in microRNA target sites of forkhead box O genes are associated with Hepatocellular Carcinoma. PLoS One 10 (3): e0119210. DOI: 10.1371/journal.pone.0119210.

Valinezhad OA, Safaralizadeh R and Kazemzadeh‐Bavili M (2014) Mechanism of miRNA‐mediated gene regulation from common downregulation to mRNA‐specific upregulation. International Journal of Genomics 2014: 970607. DOI: 10.1155/2014/970607.

Vasilopoulos Y, Cork MJ, Murphy R, et al. (2004) Genetic association between an AACC insertion in the 3′UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis. Journal of Investigative Dermatology 123: 62–66.

Vasudevan S, Tong Y and Steitz JA (2007) Switching from repression to activation: microRNAs can up‐regulate translation. Science 318: 1931–1934.

Wang G, van der Walt JM, Mayhew G, et al. (2008) Variation in the miRNA‐433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha synuclein. American Journal of Human Genetics 82: 283–289.

Wang Y, Jingzhou C, Weihua S, et al. (2015) The human myotrophin variant attenuates microRNA‐Let‐7 binding ability but not risk of left ventricular hypertrophy in human essential hypertension. PLoS One 10 (8): e0135526. DOI: 10.1371/journal.pone.0135526.

Wang Y, Du X, Zhou Z, et al. (2016) A gain‐of‐function ACTC1 3′ UTR mutation that introduces miR‐139‐5p target site may be associated with a dominant familial septal defect. Scientific Reports 6: 25404. DOI: 10.1038/srep25404.

Warf MB, Diegel JV, von Hippel PH and Berglund JA (2009) The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing. Proceedings of the National Academy of Sciences of the United States of America 106: 9203–9208.

Xiao B, Gu SM, Li MJ, et al. (2015) Rare SNP rs12731181 in the miR‐590‐3p target site of the prostaglandin F2α receptor gene confers risk for essential hypertension in the han Chinese population. Arteriosclerosis, Thrombosis, and Vascular Biology 35 (7): 1687–1695.

Zhang L and Zhao Y (2007) The regulation of Foxp3 expression in regulatory CD4 + CD25 + T cells: multiple pathways on the road. Journal of Cellular Physiology 211: 590–597.

Zhang L, Rao F, Zhang K, et al. (2007) Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk. Journal of Clinical Investigation 117: 2658–2671.

Ziebarth JD, Bhattacharya A and Cui Y (2012) Integrative analysis of somatic mutations altering microRNA targeting in cancer genomes. PLoS One 7 (10): e47137. DOI: 10.1371/journal.pone.0047137.

Zu T, Gibbens B, Doty NS, Gomes‐Pereira M, et al. (2011) Non‐ATG‐initiated translation directed by microsatellite expansions. Proceedings of the National Academy of Sciences of the United States of America 108: 260–265.

Züchner S, Wang G, Tran‐Viet KN, et al. (2006) Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. American Journal of Human Genetics 79: 365–369.

Further Reading

Chatterjee S and Pal JK (2009) Role of 5′‐and 3′‐untranslated regions of mRNAs in human diseases. Biology of the Cell 101: 251–262.

Chen JM, Férec C and Cooper DN (2006) A systematic analysis of disease‐associated variants in the 3′ regulatory regions of human protein‐coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3′ UTR variants. Human Genetics 120: 301–333.

Esquela‐Kerscher A and Slack FJ (2006) Oncomirs–microRNAs with a role in cancer. Nature Reviews. Cancer 6: 259–269.

Mirkin SM (2007) Expandable DNA repeats and human disease. Nature 447: 932–940.

Pal JK and Chatterjee S (2014) Translation regulation of gene expression and human diseases. In: Das HK (ed) Gene and its Engineering, pp. 219–233, chap. 15. New Delhi: Wiley India, chap. 4, section 2.1, pp 105–135. St Louis: CV Mosby.

Schiffmann R (2009) Fabry disease. Pharmacology & Therapeutics 122: 65–77.

Soifer HS, Rossi JJ and Sætrom P (2007) MicroRNAs in disease and potential therapeutic applications. Molecular Therapy 15: 2070–2079.

van der Vliet HJ and Nieuwenhuis EE (2007) IPEX as a result of mutations in FOXP3. Clinical and Developmental Immunology 2007: 89017. DOI: 10.1155/2007/89017.

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Pal, Jayanta K, Chatterjee, Sangeeta, and Rao, Shilpa J(Nov 2016) Pathological Variations in 3′‐Untranslated Regions of Human Genes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022450.pub2]