Pathological Mutations in 5′ Untranslated Regions of Human Genes


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.


Abernathy CO, Thomas DJ and Calderon RL (2003) Health effects and risk assessment of arsenic. Journal of Nutrition 133: 1536S–1538S.

Allerson CR, Cazzola M and Rouault TA (1999) Clinical severity and thermodynamic effects of iron‐responsive element mutations in hereditary hyperferritinemia or cataract syndrome. Journal of Biological Chemistry 274: 26439–26447.

Arrick BA, Lee AL, Grendell RL, et al. (1991) Inhibition of translation of transforming growth factor‐β3 mRNA by its 5′ untranslated region. Molecular and Cellular Biology 11: 4306–4313.

Arrick BA, Grendell RL and Griffin LA (1994) Enhanced translational efficiency of a novel transforming growth factor β3 mRNA in human breast cancer cells. Molecular and Cellular Biology 14: 619–628.

Barbosa C, Peixeiro I and Romão L (2013) Gene expression regulation by upstream open reading frames and human disease. PLoS Genetics 9 (8): e1003529. DOI: 10.1371/journal.pgen.1003529.

Bohlen AV, Bohm J, Pop R, et al. (2017) A mutation creating an upstream initiation codon in the SOX9 5′UTR causes acampomelic campomelic dysplasia. Molecular Genetics & Genomic Medicine 5 (3): 261–268.

Cao W, McMahon M, Wang B, et al. (2010) A case report of spontaneous mutation (C33>U) in the iron‐responsive element of l‐ferritin causing hyperferritinemia‐cataract syndrome. Blood Cells, Molecules & Diseases 44: 22–27.

Calvo SE, Pagliarini DJ and Mootha VK (2009) Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proceedings of the National Academy of Sciences of the United States of America 106: 7507–7512.

Cazzola M and Skoda RC (2000) Translation pathophysiology: a novel molecular mechanism of human disease. Blood 95: 3280–3288.

Cazzola M (2005) Role of ferritin and ferroportin genes in unexplained hyperferritinemia. Best Practice & Research Clinical Haematology 18: 251–263.

Chappell SA, LeQuesne JP, Paulin FE, et al. (2000) A mutation in the c‐myc‐IRES leads to enhanced internal ribosome entry in multiple myeloma: a novel mechanism of oncogene de‐regulation. Oncogene 19: 4437–4440.

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.

Cobbold LC, Wilson LA, Sawicka K, et al. (2010) Upregulated c‐myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB‐1 and YB‐1. Oncogene 29: 2884–2891.

Cremonesi L, Foglieni B, Fermo I, et al. (2003) Identification of two novel mutations in the 5′ untranslated region of H‐ferritin using denaturing high performance liquid chromatography scanning. Haematologica 88: 1110–1116.

Dodd AW, Syddall CM and Loughlin J (2013) A rare variant in the osteoarthritis‐associated locus GDF5 is functional and reveals a site that can be manipulated to modulate GDF5 expression. European Journal of Human Genetics 21: 517–521.

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

Evans JR, Mitchell SA, Spriggs KA, et al. (2003) Members of the poly (rC) binding protein family stimulate the activity of the c‐myc internal ribosome entry segment in vitro and in vivo. Oncogene 22: 8012–8020.

Fu Y, Rope R, Fargue S, et al. (2015) A mutation creating an out‐of‐frame alternative translation initiation site in the GRHPR 5′UTR causing primary hyperoxaluria type II. Clinical Genetics 88: 494–498.

Hetet G, Devaux I, Soufir N, et al. (2003) Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations. Blood 102: 1904–1910.

Holcik M and Sonenberg N (2005) Translational control in stress and apoptosis. Nature Reviews Molecular Cell Biology 6: 318–327.

Hornig NC, Beaufort C, Denzer F, et al. (2016) A recurrent germline mutation in the 5'UTR of the androgen receptor causes complete androgen insensitivity by activating aberrant uORF translation. PLoS One 11 (4): e0154158. DOI: 10.1371/journal.pone.0154158.

Hudder A and Werner R (2000) Analysis of a Charcot‐Marie‐Tooth disease mutation reveals an essential internal ribosome entry site element in the connexin‐32 gene. Journal of Biological Chemistry 275: 34586–34591.

Ionasescu VV, Searby C, Ionasescu R, et al. (1996) Mutations of the noncoding region of the connexin32 gene in X‐linked dominant Charcot‐Marie‐Tooth neuropathy. Neurology 47: 541–544.

Kato J, Fujikawa K, Kanda M, et al. (2001) A mutation, in the iron‐responsive element of H ferritin mRNA, causing autosomal dominant iron overload. American Journal of Human Genetics 69: 191–197.

Kabzinska D, Kotruchow K, Ryniewicz B, et al. (2011) Two pathogenic mutations located within the 5'‐UTR regulatory sequence of the GJB1 gene affecting initiation of transcription and translation. Acta Biochimica Polonica 58: 359–363.

Li M, Cheng TS, Ho PW, et al. (2009) 459C>T point mutation in 5′ non‐coding region of human GJB1 gene is linked to X‐linked Charcot‐Marie‐Tooth neuropathy. Journal of the Peripheral Nervous System 14: 14–21.

Luscieti S, Tolle G, Aranda J, et al. (2013) Novel mutation in the ferritin‐L iron –responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome. Orphanet Journal of Rare Diseases 8: 30–40.

Miyamoto Y, Mabuchi A, Shi D, et al. (2007) A functional polymorphism in the 5′‐UTR of GDF5 is associated with susceptibility to osteoarthritis. Nature Genetics 39: 529–533.

Morris DR and Geballe AP (2000) Upstream open reading frames as regulators of mRNA translation. Molecular and Cellular Biology 20: 8635–8642.

Muckenthaler MU, Galy B and Hentze MW (2008) Systemic iron homeostasis and the iron‐responsive element/iron‐regulatory protein (IRE/IRP) regulatory network. Annual Review of Nutrition 28: 197–213.

Mueller PP and Hinnebusch AG (1986) Multiple upstream AUG codons mediate translation control of GCN4. Cell 45: 201–207.

Örd D and Örd T (2005) Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions. Biochemical and Biophysical Research Communications 330: 210–218.

Örd T, Örd D, Kõivomägi M, et al. (2009) Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5′‐UTR. Gene 444: 24–32.

Örd T and Örd T (2017) Mammalian pseudokinase TRIB3 in normal physiology and disease: charting the progress in old and new avenues. Current Protein & Peptide Science. DOI: 10.2174/1389203718666170406124547.

Occhi G, Regazzo D, Trivellin G, et al. (2013) A novel mutation in the upstream open reading frame of the CDKN1B causes a MEN4 phenotype. PLoS Genetics 9 (3). DOI: 10.1371/journal.pgen.1003350.

Pan J, Lin J, Izzo JG, et al. (2009) Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway. Carcinogenesis 30: 785–792.

Pickering BM and Willis AE (2005) The implications of structured 5′ untranslated regions on translation and disease. Seminars in Cell & Developmental Biology 16: 39–47.

Reilly M (2007) Sorting out the inherited neuropathies. Practical Neurology 7: 93–105.

Semler O, Garbes L, Keupp K, et al. (2012) A mutation in the 5'‐UTR of IFITM5 creates an in‐frame start codon and causes autosomal dominant osteogenesis imperfecta type V with hyperplastic callus. American Journal of Human Genetics 91: 349–357.

Shi Y, Frost PJ, Hoang BQ, et al. (2008) IL‐6‐induced stimulation of c‐myc translation in multiple myeloma cells is mediated by myc internal ribosome entry site function and the RNA‐binding protein, hnRNP A1. Cancer Research 68: 10215–10222.

Southam L, Rodriguez‐Lopez J, Wilkins JM, et al. (2007) An SNP in the 5′‐UTR of GDF5 is associated with osteoarthritis susceptibility in Europeans and with in vivo differences in allelic expression in articular cartilage. Human Molecular Genetics 16: 2226–2232.

Vanita V, Hejtmancik JF, Hennies HC, et al. (2006) Sutural cataract associated with a mutation in the ferritin light chain gene (FTL) in a family of Indian origin. Molecular Vision 12: 93–99.

Wen Y, Liu Y, Xu Y, et al. (2009) Loss‐of‐function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis. Nature Genetics 41: 228–233.

Wennemers M, Bussink J, van den Beucken T, et al. (2012) Regulation of TRIB3 mRNA and protein in breast cancer. PLoS One 7 (11): e49439. DOI: 10.1371/journal.pone.0049439.

Yazar S, Franchina M, Craig JE, et al. (2016) Ferritin light chain gene mutation in a large Australian family with hereditary hyperferritinemia‐cataract syndrome. Ophthalmic Genetics 38: 171–174.

Zhou C, Zang D, Ma X, et al. (2012) Identification of a novel U2HR mutation c.14C>T in a Chinese patient with Marie Unna hereditary hypotrichosis. European Journal of Dermatology 22: 34–35.

Further Reading

Kozak M (1986) Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 44: 283–292.

Reynolds PR (2002) In sickness and in health: the importance of translational regulation. Archives of Disease in Childhood 86: 322–324.

Scheper GC, van der Knaap MS and Proud CG (2007) Translation matters: protein synthesis defects in inherited disease. Nature Reviews Genetics 8: 711–723.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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. [doi: 10.1002/9780470015902.a0022408.pub2]