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

Overview

Journal Hum Genet

Specialty Genetics

Date 2006 Jun 30

PMID 16807757

Citations 62

Authors

Jian-Min Chen

Claude Ferec

David N Cooper

Affiliations

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Abstract

In an attempt both to catalogue 3' regulatory region (3' RR)-mediated disease and to improve our understanding of the structure and function of the 3' RR, we have performed a systematic analysis of disease-associated variants in the 3' RRs of human protein-coding genes. We have previously analysed the variants that have occurred in two specific domains/motifs of the 3' untranslated region (3' UTR) as well as in the 3' flanking region. Here we have focused upon 83 known variants within the upstream sequence (USS; between the translational termination codon and the upstream core polyadenylation signal sequence) of the 3' UTR. To place these variants in their proper context, we first performed a comprehensive survey of known cis-regulatory elements within the USS and the mechanisms by which they effect post-transcriptional gene regulation. Although this survey supports the view that RNA regulatory elements function within the context of specific secondary structures, there are no general rules governing how secondary structure might exert its influence. We have therefore addressed this question by systematically evaluating both functional and non-functional (based upon in vitro reporter gene and/or electrophoretic mobility shift assay data) USS variant-containing sequences against known cis-regulatory motifs within the context of predicted RNA secondary structures. This has allowed us not only to establish a reliable and objective means to perform secondary structure prediction but also to identify consistent patterns of secondary structural change that could potentiate the discrimination of functional USS variants from their non-functional counterparts. The resulting rules were then used to infer potential functionality in the case of some of the remaining functionally uncharacterized USS variants, from their predicted secondary structures. This not only led us to identify further patterns of secondary structural change but also several potential novel cis-regulatory motifs within the 3' UTRs studied.

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References

Aranda-Abreu G, Hernandez M, Soto A, Manzo J . Possible Cis-acting signal that could be involved in the localization of different mRNAs in neuronal axons. Theor Biol Med Model. 2005; 2:33. PMC: 1215523. DOI: 10.1186/1742-4682-2-33. View

Piecyk M, Wax S, Beck A, Kedersha N, Gupta M, Maritim B . TIA-1 is a translational silencer that selectively regulates the expression of TNF-alpha. EMBO J. 2000; 19(15):4154-63. PMC: 306595. DOI: 10.1093/emboj/19.15.4154. View

Bilenoglu O, Basak A, Russell J . A 3'UTR mutation affects beta-globin expression without altering the stability of its fully processed mRNA. Br J Haematol. 2002; 119(4):1106-14. DOI: 10.1046/j.1365-2141.2002.03989.x. View

Panza F, DIntrono A, Colacicco A, Capurso C, Basile A, Torres F . LBP-1c/CP2/LSF gene polymorphism and risk of sporadic Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004; 75(1):166-8. PMC: 1757468. View

Graziano F, Kawakami K, Watanabe G, Ruzzo A, Humar B, Santini D . Association of thymidylate synthase polymorphisms with gastric cancer susceptibility. Int J Cancer. 2004; 112(6):1010-4. DOI: 10.1002/ijc.20489. View

Campa D, Zienolddiny S, Maggini V, Skaug V, Haugen A, Canzian F . Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis. 2003; 25(2):229-35. DOI: 10.1093/carcin/bgh008. View

Khabar K . The AU-rich transcriptome: more than interferons and cytokines, and its role in disease. J Interferon Cytokine Res. 2005; 25(1):1-10. DOI: 10.1089/jir.2005.25.1. View

Fang Y, van Meurs J, dAlesio A, Jhamai M, Zhao H, Rivadeneira F . Promoter and 3'-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the rotterdam study. Am J Hum Genet. 2005; 77(5):807-23. PMC: 1271389. DOI: 10.1086/497438. View

Mickleburgh I, Burtle B, Nury D, Chabanon H, Chrzanowska-Lightowlers Z, Hesketh J . Isolation and identification of a protein binding to the localization element of Metallothionein-1 mRNA. Biochem Soc Trans. 2004; 32(Pt 5):705-6. DOI: 10.1042/BST0320705. View

10.

Peeters R, van Toor H, Klootwijk W, de Rijke Y, Kuiper G, Uitterlinden A . Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J Clin Endocrinol Metab. 2003; 88(6):2880-8. DOI: 10.1210/jc.2002-021592. View

11.

Styrkarsdottir U, Cazier J, Kong A, Rolfsson O, Larsen H, Bjarnadottir E . Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol. 2003; 1(3):E69. PMC: 270020. DOI: 10.1371/journal.pbio.0000069. View

12.

Gardier S, Vincent M, Lantelme P, Rial M, Bricca G, Milon H . A1166C polymorphism of angiotensin II type 1 receptor, blood pressure and arterial stiffness in hypertension. J Hypertens. 2004; 22(11):2135-42. DOI: 10.1097/00004872-200411000-00016. View

13.

Mickleburgh I, Burtle B, Hollas H, Campbell G, Chrzanowska-Lightowlers Z, Vedeler A . Annexin A2 binds to the localization signal in the 3' untranslated region of c-myc mRNA. FEBS J. 2005; 272(2):413-21. DOI: 10.1111/j.1742-4658.2004.04481.x. View

14.

Yu J, Russell J . Structural and functional analysis of an mRNP complex that mediates the high stability of human beta-globin mRNA. Mol Cell Biol. 2001; 21(17):5879-88. PMC: 87307. DOI: 10.1128/MCB.21.17.5879-5888.2001. View

15.

Hong L, Wonodi I, Avila M, Buchanan R, McMahon R, Mitchell B . Dihydropyrimidinase-related protein 2 (DRP-2) gene and association to deficit and nondeficit schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2005; 136B(1):8-11. DOI: 10.1002/ajmg.b.30181. View

16.

Zhang H, Jia Y, Cooper J, Hale T, Zhang Z, Elbein S . Common variants in glutamine:fructose-6-phosphate amidotransferase 2 (GFPT2) gene are associated with type 2 diabetes, diabetic nephropathy, and increased GFPT2 mRNA levels. J Clin Endocrinol Metab. 2004; 89(2):748-55. DOI: 10.1210/jc.2003-031286. View

17.

Al-Maghrebi M, Brule H, Padkina M, Allen C, Holmes W, Zehner Z . The 3' untranslated region of human vimentin mRNA interacts with protein complexes containing eEF-1gamma and HAX-1. Nucleic Acids Res. 2002; 30(23):5017-28. PMC: 137969. DOI: 10.1093/nar/gkf656. View

18.

Holcik M, Liebhaber S . Four highly stable eukaryotic mRNAs assemble 3' untranslated region RNA-protein complexes sharing cis and trans components. Proc Natl Acad Sci U S A. 1997; 94(6):2410-4. PMC: 20101. DOI: 10.1073/pnas.94.6.2410. View

19.

Knowles J, Erickson L, Guy V, Sigel C, Wilder J, Maeda N . Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects. Hum Genet. 2002; 112(1):62-70. PMC: 4321888. DOI: 10.1007/s00439-002-0834-z. View

20.

Morahan G, Huang D, Ymer S, Cancilla M, Stephen K, Dabadghao P . Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nat Genet. 2001; 27(2):218-21. DOI: 10.1038/84872. View