How to cite this WIREs title:
WIREs RNA

Impact Factor: 9.957

Two sides of the same medal: Noncoding mutations reveal new pathological mechanisms and insights into the regulation of gene expression

Advanced Review

Jens Bohne, Amelie S. Wachs

Published Online: Jul 06 2020

DOI: 10.1002/wrna.1616

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Abstract Noncoding sequences constitute the major part of the human genome and also of pre‐mRNAs. Single nucleotide variants in these regions are often overlooked, but may be responsible for much of the variation of phenotypes observed. Mutations in the noncoding part of pre‐mRNAs often reveal new and meaningful insights into the regulation of cellular gene expression. Thus, the mechanistic analysis of the pathological mechanism of such mutations will both foster a deeper understanding of the disease and the underlying cellular pathways. Even synonymous mutations can cause diseases, since the primary mRNA sequence not only encodes amino acids, but also encrypts information on RNA‐binding proteins and secondary structure. In fact, the RNA sequence directs assembly of a specific mRNP complex, which in turn dictates the fate of the mRNA or regulates its biogenesis. The accumulation of genomic sequence information is increasing at a rapid pace. However, much of the diversity uncovered may not explain the phenotype of a certain syndrome or disease. For this reason, we also emphasize the value of mechanistic studies on pathological mechanisms being complementary to genome‐wide studies and bioinformatic approaches. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > 3′ End Processing RNA in Disease and Development > RNA in Disease

Cellular gene expression. (a) A cell nucleus with the nuclear membrane in black is depicted. A gene (DNA, blue line) is transcribed by RNA polymerase II (green). The emerging RNA is processed and exported through the nuclear pore. In the cytoplasm ribosomes (light blue) attach to the mRNA and translate the encoded information as shown by the growing polypeptide chain (yellow). (b) The structure of a gene is shown with the promoter in green, untranslated regions in orange, the coding sequence (CDS) in red and introns in gray. Splicing removes the introns yielding a continuous CDS

[ Normal View | Magnified View ]

Regulation of lactase expression. Upper panel: The promoter for lactase gene (LCT; green) depends on enhancer sequences (thick dark blue vertical lines) in the upstream intron 13 (gray) of the MCM6 gene. After childhood, the cytosine at pos. −13,910 becomes methylated and enhancer activity is lost (dashed arrow). Lower panel: a C>T mutation at pos. −13,910 prevents methylation and maintains enhancer activity and thus lactase expression persists into adulthood

[ Normal View | Magnified View ]

Model for miRNA‐mediated translational repression and RNA decay. An mRNA (black line) with cap (open circle) and poly (A) tail is recognized by a miRNA. The discontinuous binding is illustrated. The miRNA is incorporated into the RNA‐induced silencing complex (RISC; yellow) and its interactions (arrows) with the ribosome (light blue) and RNA decay factors (red) induces translational repression and enhanced RNA decay

[ Normal View | Magnified View ]

Splice site mutations and inhibition of cleavage and polyadenylation by U1 snRNP. (a) The scheme presents the possible outcomes of splice site mutations. The upper panel depicts the creation of new intronic splice sites that lead to the inclusion of intron fragments. In the middle panel a 5′SS mutation results in intron inclusion or activation of an alternative splice site (a. 5′SS). The bottom panel illustrates that mutations of the BPS, 3′SS or 5′SS can induce exon skipping. Exons are painted in red, introns in gray. (b) Scheme representing the possible outcome of the intron 3 5′SS mutation in the IL2RG gene. The mutation reduces the complementarity with the U1 snRNA and leads a strong decrease of the MaxEnt score. Consequently splicing of intron 3 is impaired, which results in intron retention in most of the transcripts. Due to an in‐frame stop codon, the translated protein is predicted to be truncated and presumably NMD is induced. Usage of an alternative 5′SS (a. 5′SS) leads to the insertion of a 60 nt intronic fragment in some transcripts, which are predicted to produce a IL2Rγ protein containing a 20 amino acid insertion in the extracellular domain. (c) If a 5′SS occurs close to the authentic polyadenylation signal (AAUAAA), U1 snRNP (secondary structure with associated proteins in blue) is able to inhibit the activity of cleavage factor I or II complexes (orange and yellow). This may prevent binding of cleavage and polyadenylation specificity factor (CPSF, green). The additional RNA elements are the CFIm binding site UGUA, the cleavage site (CA) and the downstream element (G/U) bound by cleavage stimulatory factor (CstF, light blue)

[ Normal View | Magnified View ]

The mRNP code. (a) The left panel depicts the genetic code with three nucleotides encoding one amino acid; in this example, leucine, and aspartic acid. The right panel illustrates that the same 6mer sequence can also be recognized by an RNA‐binding protein (RBP, green). (b) Depending on the primary sequence an mRNA assembles a unique mRNP complex as depicted by the colored RBPs and also complexes of proteins such as the cap‐binding complex (CBC, red) or the exon‐junction complex (EJC, dark blue). The poly (A) tail of mRNAs is bound by the poly (A)‐binding protein (PABP, orange)

[ Normal View | Magnified View ]

References

Abramowicz,, A., & Gos,, M. (2018). Splicing mutations in human genetic disorders: Examples, detection, and confirmation. Journal of Applied Genetics, 59, 253–268.
Almada,, A. E., Wu,, X., Kriz,, A. J., Burge,, C. B., & Sharp,, P. A. (2013). Promoter directionality is controlled by U1 snRNP and polyadenylation signals. Nature, 499, 360–363.
Andersson,, R., & Sandelin,, A. (2020). Determinants of enhancer and promoter activities of regulatory elements. Nature Reviews. Genetics, 21, 71–87.
Andresen,, B. S., Dobrowolski,, S. F., O`Reilly,, L., Muenzer,, J., McCandless,, S. E., Frazier,, D. M., … Gregersen,, N. (2001). Medium‐chain acyl‐CoA dehydrogenase (MCAD) mutations identified by MS/MS‐based prospective screening of newborns differ from those observed in patients with clinical symptoms: Identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. American Journal of Human Genetics, 68, 1408–1418.
Archibald,, J. M. (2015). Endosymbiosis and eukaryotic cell evolution. Current Biology, 25, R911–R921.
Bartel,, D. P. (2018). Metazoan MicroRNAs. Cell, 173, 20–51.
Begue,, B., Verdier,, J., Rieux‐Laucat,, F., Goulet,, O., Morali,, A., Canioni,, D., … Ruemmele,, F. M. (2011). Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. The American Journal of Gastroenterology, 106, 1544–1555.
Bennett,, C. L., Brunkow,, M. E., Ramsdell,, F., O`Briant,, K. C., Zhu,, Q., Fuleihan,, R. L., … Chance,, P. F. (2001). A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA%3EAAUGAA) leads to the IPEX syndrome. Immunogenetics, 53, 435–439.
Berg,, M. G., Singh,, L. N., Younis,, I., Liu,, Q., Pinto,, A. M., Kaida,, D., … Dreyfuss,, G. (2012). U1 snRNP determines mRNA length and regulates isoform expression. Cell, 150, 53–64.
Berkovits,, B. D., & Mayr,, C. (2015). Alternative 3` UTRs act as scaffolds to regulate membrane protein localization. Nature, 522, 363–367.
Bohn,, G., Allroth,, A., Brandes,, G., Thiel,, J., Glocker,, E., Schaffer,, A. A., … Klein,, C. (2007). A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nature Medicine, 13, 38–45.
Boyle,, E. A., Li,, Y. I., & Pritchard,, J. K. (2017). An expanded view of complex traits: From polygenic to Omnigenic. Cell, 169, 1177–1186.
Brugiolo,, M., Herzel,, L., & Neugebauer,, K. M. (2013). Counting on co‐transcriptional splicing. F1000Prime Reports, 5, 9.
Buckley,, R. H. (2002). Primary immunodeficiency diseases: Dissectors of the immune system. Immunological Reviews, 185, 206–219.
Castello,, A., Fischer,, B., Hentze,, M. W., & Preiss,, T. (2013). RNA‐binding proteins in Mendelian disease. Trends in Genetics, 29, 318–327.
Cech,, T. R., & Steitz,, J. A. (2014). The noncoding RNA revolution‐trashing old rules to forge new ones. Cell, 157, 77–94.
Chen,, C. Y., & Shyu,, A. B. (1995). AU‐rich elements: Characterization and importance in mRNA degradation. Trends in Biochemical Sciences, 20, 465–470.
Chiba‐Falek,, O., Kerem,, E., Shoshani,, T., Aviram,, M., Augarten,, A., Bentur,, L., … Kerem,, B. (1998). The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C%3ET mutation. Genomics, 53, 276–283.
Chiu,, A. C., Suzuki,, H. I., Wu,, X., Mahat,, D. B., Kriz,, A. J., & Sharp,, P. A. (2018). Transcriptional pause sites delineate stable nucleosome‐associated premature Polyadenylation suppressed by U1 snRNP. Molecular Cell, 69, 648–663.e7.
Cipolla,, G. A., Park,, J. K., de Oliveira,, L. A., Lobo‐Alves,, S. C., de Almeida,, R. C., Farias,, T. D., … Petzl‐Erler,, M. L. (2016). A 3`UTR polymorphism marks differential KLRG1 mRNA levels through disruption of a miR‐584‐5p binding site and associates with pemphigus foliaceus susceptibility. Biochimica et Biophysica Acta, 1859, 1306–1313.
Cleary,, J. D., Pattamatta,, A., & Ranum,, L. P. W. (2018). Repeat‐associated non‐ATG (RAN) translation. The Journal of Biological Chemistry, 293, 16127–16141.
Cook,, K. B., Kazan,, H., Zuberi,, K., Morris,, Q., & Hughes,, T. R. (2011). RBPDB: A database of RNA‐binding specificities. Nucleic Acids Research, 39, D301–D308.
Corley,, M., Solem,, A., Phillips,, G., Lackey,, L., Ziehr,, B., Vincent,, H. A., … Laederach,, A. (2017). An RNA structure‐mediated, posttranscriptional model of human alpha‐1‐antitrypsin expression. Proceedings of the National Academy of Sciences of the United States of America, 114, E10244–E10253.
de Leeuw,, R., Gruenbaum,, Y., & Medalia,, O. (2018). Nuclear Lamins: Thin filaments with major functions. Trends in Cell Biology, 28, 34–45.
Derti,, A., Garrett‐Engele,, P., Macisaac,, K. D., Stevens,, R. C., Sriram,, S., Chen,, R., … Babak,, T. (2012). A quantitative atlas of polyadenylation in five mammals. Genome Research, 22, 1173–1183.
di Iulio,, J., Bartha,, I., Wong,, E. H. M., Yu,, H. C., Lavrenko,, V., Yang,, D., … Telenti,, A. (2018). The human noncoding genome defined by genetic diversity. Nature Genetics, 50, 333–337.
di Paola,, R., Frittitta,, L., Miscio,, G., Bozzali,, M., Baratta,, R., Centra,, M., … Trischitta,, V. (2002). A variation in 3` UTR of hPTP1B increases specific gene expression and associates with insulin resistance. American Journal of Human Genetics, 70, 806–812.
Dominguez,, D., Freese,, P., Alexis,, M. S., Su,, A., Hochman,, M., Palden,, T., … Burge,, C. B. (2018). Sequence, structure, and context preferences of human RNA binding proteins. Molecular Cell, 70, 854–867.e9.
Eliscovich,, C., & Singer,, R. H. (2017). RNP transport in cell biology: The long and winding road. Current Opinion in Cell Biology, 45, 38–46.
Fabian,, M. R., Sonenberg,, N., & Filipowicz,, W. (2010). Regulation of mRNA translation and stability by microRNAs. Annual Review of Biochemistry, 79, 351–379.
Fahiminiya,, S., Al‐Jallad,, H., Majewski,, J., Palomo,, T., Moffatt,, P., Roschger,, P., … Rauch,, F. (2015). A polyadenylation site variant causes transcript‐specific BMP1 deficiency and frequent fractures in children. Human Molecular Genetics, 24, 516–524.
Ferraresi,, P., Marchetti,, G., Legnani,, C., Cavallari,, E., Castoldi,, E., Mascoli,, F., … Bernardi,, F. (1997). The heterozygous 20210 G/a prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 17, 2418–2422.
Finotti,, A., Fabbri,, E., Lampronti,, I., Gasparello,, J., Borgatti,, M., & Gambari,, R. (2019). MicroRNAs and long non‐coding RNAs in genetic diseases. Molecular Diagnosis %26 Therapy, 23, 155–171.
Fox‐Walsh,, K. L., & Hertel,, K. J. (2009). Splice‐site pairing is an intrinsically high fidelity process. Proceedings of the National Academy of Sciences of the United States of America, 106, 1766–1771.
Fu,, Y. H., Kuhl,, D. P., Pizzuti,, A., Pieretti,, M., Sutcliffe,, J. S., Richards,, S., … Caskey,, C. T. (1991). Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell, 67, 1047–1058.
Furth,, P. A., Choe,, W. T., Rex,, J. H., Byrne,, J. C., & Baker,, C. C. (1994). Sequences homologous to 5′ splice sites are required for the inhibitory activity of papillomavirus late 3′ untranslated regions. Molecular and Cellular Biology, 14, 5278–5289.
Ganser,, L. R., Kelly,, M. L., Herschlag,, D., & Al‐Hashimi,, H. M. (2019). The roles of structural dynamics in the cellular functions of RNAs. Nature Reviews. Molecular Cell Biology, 20, 474–489.
Gehring,, N. H., Frede,, U., Neu‐Yilik,, G., Hundsdoerfer,, P., Vetter,, B., Hentze,, M. W., & Kulozik,, A. E. (2001). Increased efficiency of mRNA 3′ end formation: A new genetic mechanism contributing to hereditary thrombophilia. Nature Genetics, 28, 389–392.
Gerbault,, P., Liebert,, A., Itan,, Y., Powell,, A., Currat,, M., Burger,, J., … Thomas,, M. G. (2011). Evolution of lactase persistence: An example of human niche construction. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 366, 863–877.
Ginn,, S. L., Smyth,, C., Wong,, M., Bennetts,, B., Rowe,, P. B., & Alexander,, I. E. (2004). A novel splice‐site mutation in the common gamma chain (gammac) gene IL2RG results in X‐linked severe combined immunodeficiency with an atypical NK+ phenotype. Human Mutation, 23, 522–523.
Glocker,, E. O., Kotlarz,, D., Boztug,, K., Gertz,, E. M., Schaffer,, A. A., Noyan,, F., … Klein,, C. (2009). Inflammatory bowel disease and mutations affecting the interleukin‐10 receptor. The New England Journal of Medicine, 361, 2033–2045.
Graham,, R. R., Kyogoku,, C., Sigurdsson,, S., Vlasova,, I. A., Davies,, L. R., Baechler,, E. C., … Altshuler,, D. (2007). Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proceedings of the National Academy of Sciences of the United States of America, 104, 6758–6763.
Greene,, N. D., & Copp,, A. J. (2014). Neural tube defects. Annual Review of Neuroscience, 37, 221–242.
Grigelioniene,, G., Suzuki,, H. I., Taylan,, F., Mirzamohammadi,, F., Borochowitz,, Z. U., Ayturk,, U. M., … Kobayashi,, T. (2019). Gain‐of‐function mutation of microRNA‐140 in human skeletal dysplasia. Nature Medicine, 25, 583–590.
Gruber,, A. J., & Zavolan,, M. (2019). Alternative cleavage and polyadenylation in health and disease. Nature Reviews. Genetics, 20, 599–614.
Gunderson,, S. I., Polycarpou‐Schwarz,, M., & Mattaj,, I. W. (1998). U1 snRNP inhibits pre‐mRNA polyadenylation through a direct interaction between U1 70K and poly (a) polymerase. Molecular Cell, 1, 255–264.
Hagerman,, R. J., Leehey,, M., Heinrichs,, W., Tassone,, F., Wilson,, R., Hills,, J., … Hagerman,, P. J. (2001). Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology, 57, 127–130.
Hernandez,, G., Osnaya,, V. G., & Perez‐Martinez,, X. (2019). Conservation and variability of the AUG initiation codon context in eukaryotes. Trends in Biochemical Sciences, 44, 1009–1021.
Herzel,, L., Ottoz,, D. S. M., Alpert,, T., & Neugebauer,, K. M. (2017). Splicing and transcription touch base: Co‐transcriptional spliceosome assembly and function. Nature Reviews. Molecular Cell Biology, 18, 637–650.
Higgs,, D. R., Goodbourn,, S. E., Lamb,, J., Clegg,, J. B., Weatherall,, D. J., & Proudfoot,, N. J. (1983). Alpha‐thalassaemia caused by a polyadenylation signal mutation. Nature, 306, 398–400.
Highsmith,, W. E., Burch,, L. H., Zhou,, Z., Olsen,, J. C., Boat,, T. E., Spock,, A., … Silverman,, L. M. (1994). A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. The New England Journal of Medicine, 331, 974–980.
Hinnebusch,, A. G., Ivanov,, I. P., & Sonenberg,, N. (2016). Translational control by 5′‐untranslated regions of eukaryotic mRNAs. Science, 352, 1413–1416.
Hoque,, M., Li,, W., & Tian,, B. (2014). Accurate mapping of cleavage and polyadenylation sites by 3′ region extraction and deep sequencing. Methods in Molecular Biology, 1125, 119–129.
Hsu,, A. P., Fleisher,, T. A., & Niemela,, J. E. (2009). Mutation analysis in primary immunodeficiency diseases: Case studies. Current Opinion in Allergy and Clinical Immunology, 9, 517–524.
Hughes,, A. E., Bradley,, D. T., Campbell,, M., Lechner,, J., Dash,, D. P., Simpson,, D. A., & Willoughby,, C. E. (2011). Mutation altering the miR‐184 seed region causes familial keratoconus with cataract. American Journal of Human Genetics, 89, 628–633.
Illig,, D., Navratil,, M., Kelecic,, J., Conca,, R., Hojsak,, I., Jadresin,, O., … Kotlarz,, D. (2019). Alternative splicing rescues loss of common gamma chain function and results in IL‐21R‐like deficiency. Journal of Clinical Immunology, 39, 207–215.
Itan,, Y., Powell,, A., Beaumont,, M. A., Burger,, J., & Thomas,, M. G. (2009). The origins of lactase persistence in Europe. PLoS Computational Biology, 5, e1000491.
Jacobson,, E. M., Concepcion,, E., Oashi,, T., & Tomer,, Y. (2005). A graves’ disease‐associated Kozak sequence single‐nucleotide polymorphism enhances the efficiency of CD40 gene translation: A case for translational pathophysiology. Endocrinology, 146, 2684–2691.
Kaida,, D., Berg,, M. G., Younis,, I., Kasim,, M., Singh,, L. N., Wan,, L., & Dreyfuss,, G. (2010). U1 snRNP protects pre‐mRNAs from premature cleavage and polyadenylation. Nature, 468, 664–668.
Katz,, Z. B., Wells,, A. L., Park,, H. Y., Wu,, B., Shenoy,, S. M., & Singer,, R. H. (2012). Beta‐Actin mRNA compartmentalization enhances focal adhesion stability and directs cell migration. Genes %26 Development, 26, 1885–1890.
Khan,, S. G., Metin,, A., Gozukara,, E., Inui,, H., Shahlavi,, T., Muniz‐Medina,, V., … Kraemer,, K. H. (2004). Two essential splice lariat branchpoint sequences in one intron in a xeroderma pigmentosum DNA repair gene: Mutations result in reduced XPC mRNA levels that correlate with cancer risk. Human Molecular Genetics, 13, 343–352.
Khan,, S. G., Yamanegi,, K., Zheng,, Z. M., Boyle,, J., Imoto,, K., Oh,, K. S., … Kraemer,, K. H. (2010). XPC branch‐point sequence mutations disrupt U2 snRNP binding, resulting in abnormal pre‐mRNA splicing in xeroderma pigmentosum patients. Human Mutation, 31, 167–175.
Khanna,, A., & Stamm,, S. (2010). Regulation of alternative splicing by short non‐coding nuclear RNAs. RNA Biology, 7, 480–485.
Kishore,, S., Khanna,, A., Zhang,, Z., Hui,, J., Balwierz,, P. J., Stefan,, M., … Stamm,, S. (2010). The snoRNA MBII‐52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing. Human Molecular Genetics, 19, 1153–1164.
Kishore,, S., & Stamm,, S. (2006). The snoRNA HBII‐52 regulates alternative splicing of the serotonin receptor 2C. Science, 311, 230–232.
Kiss,, T. (2002). Small nucleolar RNAs: an abundant group of noncoding RNAs with diverse cellular functions. Cell, 109, 145–148.
Kotlarz,, D., Beier,, R., Murugan,, D., Diestelhorst,, J., Jensen,, O., Boztug,, K., … Klein,, C. (2012). Loss of interleukin‐10 signaling and infantile inflammatory bowel disease: Implications for diagnosis and therapy. Gastroenterology, 143, 347–355.
Kozak,, M. (1981). Possible role of flanking nucleotides in recognition of the AUG initiator codon by eukaryotic ribosomes. Nucleic Acids Research, 9, 5233–5252.
Kozak,, M. (2005). Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene, 361, 13–37.
Krooss,, S., Werwitzke,, S., Kopp,, J., Rovai,, A., Varnholt,, D., Wachs,, A. S., … Bohne,, J. (2020). Pathological mechanism and antisense oligonucleotide‐mediated rescue of a non‐coding variant suppressing factor 9 RNA biogenesis leading to hemophilia B. PLoS Genetics, 16, e1008690.
Kuehn,, H. S., Ouyang,, W., Lo,, B., Deenick,, E. K., Niemela,, J. E., Avery,, D. T., … Uzel,, G. (2014). Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science, 345, 1623–1627.
Kuspert,, M., Murakawa,, Y., Schaffler,, K., Vanselow,, J. T., Wolf,, E., Juranek,, S., … Fischer,, U. (2015). LARP4B is an AU‐rich sequence associated factor that promotes mRNA accumulation and translation. RNA, 21, 1294–1305.
Labrie,, V., Buske,, O. J., Oh,, E., Jeremian,, R., Ptak,, C., Gasiunas,, G., … Petronis,, A. (2016). Lactase nonpersistence is directed by DNA‐variation‐dependent epigenetic aging. Nature Structural %26 Molecular Biology, 23, 566–573.
Lai,, D., Proctor,, J. R., & Meyer,, I. M. (2013). On the importance of cotranscriptional RNA structure formation. RNA, 19, 1461–1473.
Lander,, E. S., Linton,, L. M., Birren,, B., Nusbaum,, C., Zody,, M. C., Baldwin,, J., … International Human Genome Sequencing Consortium. (2001). Initial sequencing and analysis of the human genome. Nature, 409, 860–921.
Langemeier,, J., Radtke,, M., & Bohne,, J. (2013). U1 snRNP‐mediated poly (A) site suppression: Beneficial and deleterious for mRNA fate. RNA Biology, 10, 180–184.
Langemeier,, J., Schrom,, E. M., Rabner,, A., Radtke,, M., Zychlinski,, D., Saborowski,, A., … Bohne,, J. (2012). A complex immunodeficiency is based on U1 snRNP‐mediated poly (a) site suppression. The EMBO Journal, 31, 4035–4044.
Leppek,, K., Das,, R., & Barna,, M. (2018). Author correction: Functional 5` UTR mRNA structures in eukaryotic translation regulation and how to find them. Nature Reviews. Molecular Cell Biology, 19, 673.
Lim,, C. K., Abolhassani,, H., Appelberg,, S. K., Sundin,, M., & Hammarstrom,, L. (2019). IL2RG hypomorphic mutation: Identification of a novel pathogenic mutation in exon 8 and a review of the literature. Allergy, Asthma and Clinical Immunology, 15, 2.
Liquori,, C. L., Ricker,, K., Moseley,, M. L., Jacobsen,, J. F., Kress,, W., Naylor,, S. L., … Ranum,, L. P. (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science, 293, 864–867.
Long,, J. C., & Caceres,, J. F. (2009). The SR protein family of splicing factors: Master regulators of gene expression. The Biochemical Journal, 417, 15–27.
Lopez Castel,, A., Cleary,, J. D., & Pearson,, C. E. (2010). Repeat instability as the basis for human diseases and as a potential target for therapy. Nature Reviews. Molecular Cell Biology, 11, 165–170.
Louzada,, S., Lopes,, M., Ferreira,, D., Adega,, F., Escudeiro,, A., Gama‐Carvalho,, M., & Chaves,, R. (2020). Decoding the role of satellite DNA in genome architecture and plasticity‐an evolutionary and clinical affair. Genes (Basel), 11, 1–21.
Marchand,, V., Mereau,, A., Jacquenet,, S., Thomas,, D., Mougin,, A., Gattoni,, R., … Branlant,, C. (2002). A Janus splicing regulatory element modulates HIV‐1 tat and rev mRNA production by coordination of hnRNP A1 cooperative binding. Journal of Molecular Biology, 323, 629–652.
Martin,, K. C., & Ephrussi,, A. (2009). mRNA localization: Gene expression in the spatial dimension. Cell, 136, 719–730.
Mayr,, C. (2017). Regulation by 3`‐Untranslated regions. Annual Review of Genetics, 51, 171–194.
Mencia,, A., Modamio‐Hoybjor,, S., Redshaw,, N., Morin,, M., Mayo‐Merino,, F., Olavarrieta,, L., … Moreno‐Pelayo,, M. A. (2009). Mutations in the seed region of human miR‐96 are responsible for nonsyndromic progressive hearing loss. Nature Genetics, 41, 609–613.
Mercer,, T. R., Clark,, M. B., Andersen,, S. B., Brunck,, M. E., Haerty,, W., Crawford,, J., … Mattick,, J. S. (2015). Genome‐wide discovery of human splicing branchpoints. Genome Research, 25, 290–303.
Minguzzi,, S., Selcuklu,, S. D., Spillane,, C., & Parle‐McDermott,, A. (2014). An NTD‐associated polymorphism in the 3` UTR of MTHFD1L can affect disease risk by altering miRNA binding. Human Mutation, 35, 96–104.
Mofatteh,, M., & Bullock,, S. L. (2017). SnapShot: Subcellular mRNA localization. Cell, 169, 178–178 e171.
Morle,, F., Lopez,, B., Henni,, T., & Godet,, J. (1985). Alpha‐Thalassaemia associated with the deletion of two nucleotides at position ‐2 and ‐3 preceding the AUG codon. The EMBO Journal, 4, 1245–1250.
Morriss,, G. R., & Cooper,, T. A. (2017). Protein sequestration as a normal function of long noncoding RNAs and a pathogenic mechanism of RNAs containing nucleotide repeat expansions. Human Genetics, 136, 1247–1263.
Murugan,, D., Albert,, M. H., Langemeier,, J., Bohne,, J., Puchalka,, J., Jarvinen,, P. M., … Kotlarz,, D.. (2014) Very early onset inflammatory bowel disease associated with aberrant trafficking of IL‐10R1 and cure by T cell replete Haploidentical bone marrow transplantation. Journal of Clinical Immunology, 34, 331–339.
Neto,, J. L., Lee,, J. M., Afridi,, A., Gillis,, T., Guide,, J. R., Dempsey,, S., … Pinto,, R. M. (2017). Genetic contributors to intergenerational CAG repeat instability in Huntington`s disease Knock‐in mice. Genetics, 205, 503–516.
Nielsen,, K. B., Sorensen,, S., Cartegni,, L., Corydon,, T. J., Doktor,, T. K., Schroeder,, L. D., … Andresen,, B. S. (2007). Seemingly neutral polymorphic variants may confer immunity to splicing‐inactivating mutations: A synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. American Journal of Human Genetics, 80, 416–432.
Noguchi,, M., Yi,, H., Rosenblatt,, H. M., Filipovich,, A. H., Adelstein,, S., Modi,, W. S., … Leonard,, W. J. (1993). Interleukin‐2 receptor gamma chain mutation results in X‐linked severe combined immunodeficiency in humans. Cell, 73, 147–157.
Oh,, J. M., Di,, C., Venters,, C. C., Guo,, J., Arai,, C., So,, B. R., … Dreyfuss,, G. (2017). U1 snRNP telescripting regulates a size‐function‐stratified human genome. Nature Structural %26 Molecular Biology, 24, 993–999.
Ong,, A. A. L., Tan,, J., Bhadra,, M., Dezanet,, C., Patil,, K. M., Chong,, M. S., … Chen,, G. (2019). RNA secondary structure‐based Design of Antisense Peptide Nucleic Acids for modulating disease‐associated aberrant tau pre‐mRNA alternative splicing. Molecules, 24, 1–14.
Orkin,, S. H., Cheng,, T. C., Antonarakis,, S. E., & Kazazian,, H. H., Jr. (1985). Thalassemia due to a mutation in the cleavage‐polyadenylation signal of the human beta‐globin gene. The EMBO Journal, 4, 453–456.
Orr,, H. T., & Zoghbi,, H. Y. (2007). Trinucleotide repeat disorders. Annual Review of Neuroscience, 30, 575–621.
Paz,, I., Kosti,, I., Ares,, M., Jr., Cline,, M., & Mandel‐Gutfreund,, Y. (2014). RBPmap: A web server for mapping binding sites of RNA‐binding proteins. Nucleic Acids Research, 42, W361–W367.
Polychronakos,, C. (2012). Gene expression as a quantitative trait: What about translation? Journal of Medical Genetics, 49, 554–557.
Poort,, S. R., Rosendaal,, F. R., Reitsma,, P. H., & Bertina,, R. M. (1996). A common genetic variation in the 3′‐untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood, 88, 3698–3703.
Purswani,, P., Meehan,, C. A., Kuehn,, H. S., Chang,, Y., Dasso,, J. F., Meyer,, A. K., … Walter,, J. E. (2019). Two unique cases of X‐linked SCID: A diagnostic challenge in the era of newborn screening. Frontiers in Pediatrics, 7, 55.
Qian,, W., & Liu,, F. (2014). Regulation of alternative splicing of tau exon 10. Neuroscience Bulletin, 30, 367–377.
Ranum,, L. P., & Cooper,, T. A. (2006). RNA‐mediated neuromuscular disorders. Annual Review of Neuroscience, 29, 259–277.
Rochman,, Y., Spolski,, R., & Leonard,, W. J. (2009). New insights into the regulation of T cells by gamma (c) family cytokines. Nature Reviews. Immunology, 9, 480–490.
Rogaev,, E. I., Grigorenko,, A. P., Faskhutdinova,, G., Kittler,, E. L., & Moliaka,, Y. K. (2009). Genotype analysis identifies the cause of the "royal disease". Science, 326, 817.
Rogozin,, I. B., Carmel,, L., Csuros,, M., & Koonin,, E. V. (2012). Origin and evolution of spliceosomal introns. Biology Direct, 7, 11.
Rund,, D., Dowling,, C., Najjar,, K., Rachmilewitz,, E. A., Kazazian,, H. H., Jr., & Oppenheim,, A. (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.
Runte,, M., Varon,, R., Horn,, D., Horsthemke,, B., & Buiting,, K. (2005). Exclusion of the C/D box snoRNA gene cluster HBII‐52 from a major role in Prader‐Willi syndrome. Human Genetics, 116, 228–230.
Sahoo,, T., del Gaudio,, D., German,, J. R., Shinawi,, M., Peters,, S. U., Person,, R. E., … Beaudet,, A. L. (2008). Prader‐Willi phenotype caused by paternal deficiency for the HBII‐85 C/D box small nucleolar RNA cluster. Nature Genetics, 40, 719–721.
Schubert,, D., Bode,, C., Kenefeck,, R., Hou,, T. Z., Wing,, J. B., Kennedy,, A., … Grimbacher,, B. (2014). Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nature Medicine, 20, 1410–1416.
Shabalina,, S. A., Spiridonov,, N. A., & Kashina,, A. (2013). Sounds of silence: Synonymous nucleotides as a key to biological regulation and complexity. Nucleic Acids Research, 41, 2073–2094.
Sheets,, M. D., Ogg,, S. C., & Wickens,, M. P. (1990). Point mutations in AAUAAA and the poly (a) addition site: Effects on the accuracy and efficiency of cleavage and polyadenylation in vitro. Nucleic Acids Research, 18, 5799–5805.
Shi,, Y., & Manley,, J. L. (2015). The end of the message: Multiple protein‐RNA interactions define the mRNA polyadenylation site. Genes %26 Development, 29, 889–897.
Shilo,, A., Tosto,, F. A., Rausch,, J. W., Le Grice,, S. F. J., & Misteli,, T. (2019). Interplay of primary sequence, position and secondary RNA structure determines alternative splicing of LMNA in a pre‐mature aging syndrome. Nucleic Acids Research, 47, 5922–5935.
Shuai,, S., Suzuki,, H., Diaz‐Navarro,, A., Nadeu,, F., Kumar,, S. A., Gutierrez‐Fernandez,, A., … Stein,, L. D. (2019). The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature, 574, 712–716.
So,, B. R., Di,, C., Cai,, Z., Venters,, C. C., Guo,, J., Oh,, J. M., … Dreyfuss,, G. (2019). A complex of U1 snRNP with cleavage and polyadenylation factors controls telescripting, regulating mrna transcription in human cells. Molecular Cell, 76, 590–599.e4.
Soemedi,, R., Cygan,, K. J., Rhine,, C. L., Wang,, J., Bulacan,, C., Yang,, J., … Fairbrother,, W. G. (2017). Pathogenic variants that alter protein code often disrupt splicing. Nature Genetics, 49, 848–855.
Solaymani‐Mohammadi,, S., Eckmann,, L., & Singer,, S. M. (2019). Interleukin (IL)‐21 in inflammation and immunity during parasitic diseases. Frontiers in Cellular and Infection Microbiology, 9, 401.
Sugamura,, K., Asao,, H., Kondo,, M., Tanaka,, N., Ishii,, N., Ohbo,, K., … Takeshita,, T. (1996). The interleukin‐2 receptor gamma chain: Its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annual Review of Immunology, 14, 179–205.
Sun,, K., & Lai,, E. C. (2013). Adult‐specific functions of animal microRNAs. Nature Reviews. Genetics, 14, 535–548.
Sun,, L., Fazal,, F. M., Li,, P., Broughton,, J. P., Lee,, B., Tang,, L., … Zhang,, Q. C. (2019). RNA structure maps across mammalian cellular compartments. Nature Structural %26 Molecular Biology, 26, 322–330.
Suzuki,, H., Kumar,, S. A., Shuai,, S., Diaz‐Navarro,, A., Gutierrez‐Fernandez,, A., de Antonellis,, P., … Taylor,, M. D. (2019). Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature, 574, 707–711.
Swallow,, D. M., & Troelsen,, J. T. (2016). Escape from epigenetic silencing of lactase expression is triggered by a single‐nucleotide change. Nature Structural %26 Molecular Biology, 23, 505–507.
Tapia‐Llanos,, R., Munoz‐Valle,, J. F., Roman‐Fernandez,, I. V., Marin‐Rosales,, M., Salazar‐Camarena,, D. C., Cruz,, A., … Palafox‐Sanchez,, C. A. (2019). Association of soluble CD40 levels with −1 C %3E T CD40 polymorphism and chronic kidney disease in systemic lupus erythematosus. Molecular Genetics %26 Genomic Medicine, 7, e1014.
Tian,, B., & Manley,, J. L. (2017). Alternative polyadenylation of mRNA precursors. Nature Reviews. Molecular Cell Biology, 18, 18–30.
Ueda,, H., Howson,, J. M., Esposito,, L., Heward,, J., Snook,, H., Chamberlain,, G., … Gough,, S. C. (2003). Association of the T‐cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature, 423, 506–511.
Venters,, C. C., Oh,, J. M., Di,, C., So,, B. R., & Dreyfuss,, G. (2019). U1 snRNP Telescripting: Suppression of premature transcription termination in introns as a new layer of gene regulation. Cold Spring Harbor Perspectives in Biology, 11, 1–17.
Vielhaber,, E., Jacobson,, D. P., Ketterling,, R. P., Liu,, J. Z., & Sommer,, S. S. (1993). A mutation in the 3′ untranslated region of the factor IX gene in four families with hemophilia B. Human Molecular Genetics, 2, 1309–1310.
Wahl,, M. C., Will,, C. L., & Luhrmann,, R. (2009). The spliceosome: Design principles of a dynamic RNP machine. Cell, 136, 701–718.
Wang,, Z., & Burge,, C. B. (2008). Splicing regulation: From a parts list of regulatory elements to an integrated splicing code. RNA, 14, 802–813.
Wenstrup,, R. J., Shrago‐Howe,, A. W., Lever,, L. W., Phillips,, C. L., Byers,, P. H., & Cohn,, D. H. (1991). The effects of different cysteine for glycine substitutions within alpha 2 (I) chains. Evidence of distinct structural domains within the type I collagen triple helix. The Journal of Biological Chemistry, 266, 2590–2594.
Will,, C. L., & Luhrmann,, R. (2011). Spliceosome structure and function. Cold Spring Harbor Perspectives in Biology, 3, 1–25.
Xiong,, H. Y., Alipanahi,, B., Lee,, L. J., Bretschneider,, H., Merico,, D., Yuen,, R. K., … Frey,, B. J. (2015). RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Science, 347, 1254806.
Yeo,, G., & Burge,, C. B. (2004). Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. Journal of Computational Biology, 11, 377–394.
Yoon,, O. K., Hsu,, T. Y., Im,, J. H., & Brem,, R. B. (2012). Genetics and regulatory impact of alternative polyadenylation in human B‐lymphoblastoid cells. PLoS Genetics, 8, e1002882.

Further Reading

Oeffinger,, M., & Zenklusen,, D. (2019). The Biology of mRNA: Structure and Function. Advances in Experimental Medicine and Biology (Vol. 1203). Cham: Springer. https://doi.org/10.1007/978-3-030-31434-7

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts