Advertisement

Human Genetics

, Volume 136, Issue 9, pp 1093–1111 | Cite as

Deep intronic mutations and human disease

  • Rita Vaz-Drago
  • Noélia Custódio
  • Maria Carmo-Fonseca
Review
Part of the following topical collections:
  1. RNA Processing

Abstract

Next-generation sequencing has revolutionized clinical diagnostic testing. Yet, for a substantial proportion of patients, sequence information restricted to exons and exon–intron boundaries fails to identify the genetic cause of the disease. Here we review evidence from mRNA analysis and entire genomic sequencing indicating that pathogenic mutations can occur deep within the introns of over 75 disease-associated genes. Deleterious DNA variants located more than 100 base pairs away from exon–intron junctions most commonly lead to pseudo-exon inclusion due to activation of non-canonical splice sites or changes in splicing regulatory elements. Additionally, deep intronic mutations can disrupt transcription regulatory motifs and non-coding RNA genes. This review aims to highlight the importance of studying variation in deep intronic sequence as a cause of monogenic disorders as well as hereditary cancer syndromes.

Keywords

Splice Site Fabry Disease Duchenne Muscular Dystrophy Splice Enhancer Androgen Insensitivity Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank Joana Tavares and Isabel Vaz for critical reading of the manuscript. This work was supported by Fundação para a Ciência e a Tecnologia (Grant PTDC/BEX-BCM/5899/2014 and fellowship SFRH/BD/90231/2012 to R.V.D).

References

  1. Abeliovich D, Lavon IP, Lerer I, Cohen T, Springer C, Avital A, Cutting GR (1992) Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population. Am J Hum Genet 51:951–956PubMedPubMedCentralGoogle Scholar
  2. Akker SA, Misra S, Aslam S, Morgan EL, Smith PJ, Khoo B, Chew SL (2007) Pre-spliceosomal binding of U1 small nuclear ribonucleoprotein (RNP) and heterogenous nuclear RNP E1 is associated with suppression of a growth hormone receptor pseudoexon. Mol Endocrinol 21:2529–2540. doi: 10.1210/me.2007-0038 PubMedCrossRefGoogle Scholar
  3. Akman HO et al (2015) Deep intronic GBE1 mutation in manifesting heterozygous patients with adult polyglucosan body disease. JAMA Neurol 72:441–445. doi: 10.1001/jamaneurol.2014.4496 PubMedCrossRefGoogle Scholar
  4. Albuisson J et al (2011) Identification of two novel mutations in Shh long-range regulator associated with familial pre-axial polydactyly. Clin Genet 79:371–377. doi: 10.1111/j.1399-0004.2010.01465.x PubMedCrossRefGoogle Scholar
  5. Anczukow O et al (2012) BRCA2 deep intronic mutation causing activation of a cryptic exon: opening toward a new preventive therapeutic strategy. Clin Cancer Res Off J Am Assoc Can Res 18:4903–4909. doi: 10.1158/1078-0432.CCR-12-1100 CrossRefGoogle Scholar
  6. Antonellis A et al (2010) A rare myelin protein zero (MPZ) variant alters enhancer activity in vitro and in vivo. PLoS One 5:e14346. doi: 10.1371/journal.pone.0014346 PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bagnall RD, Waseem NH, Green PM, Colvin B, Lee C, Giannelli F (1999) Creation of a novel donor splice site in intron 1 of the factor VIII gene leads to activation of a 191 bp cryptic exon in two haemophilia A patients. Br J Haematol 107:766–771PubMedCrossRefGoogle Scholar
  8. Balz V, Prisack HB, Bier H, Bojar H (2002) Analysis of BRCA1, TP53, and TSG101 germline mutations in German breast and/or ovarian cancer families. Cancer Genet Cytogenet 138:120–127PubMedCrossRefGoogle Scholar
  9. Barash Y et al (2010) Deciphering the splicing code. Nature 465:53–59. doi: 10.1038/nature09000 PubMedCrossRefGoogle Scholar
  10. Baskin B, Gibson WT, Ray PN (2011) Duchenne muscular dystrophy caused by a complex rearrangement between intron 43 of the DMD gene and chromosome 4. Neuromusc Disord NMD 21:178–182. doi: 10.1016/j.nmd.2010.11.008 PubMedCrossRefGoogle Scholar
  11. Bauwens M et al (2015) An augmented ABCA4 screen targeting noncoding regions reveals a deep intronic founder variant in Belgian Stargardt patients. Hum Mutat 36:39–42. doi: 10.1002/humu.22716 PubMedCrossRefGoogle Scholar
  12. Bax NM et al (2015) Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant. Hum Mutat 36:43–47. doi: 10.1002/humu.22717 PubMedCrossRefGoogle Scholar
  13. Becker PW et al (2016) An intronic Flk1 enhancer directs arterial-specific expression via RBPJ-mediated venous repression. Arterioscler Thromb Vasc Biol 36:1209–1219. doi: 10.1161/ATVBAHA.116.307517 PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bellin M, Marchetto MC, Gage FH, Mummery CL (2012) Induced pluripotent stem cells: the new patient? Nat Rev Mol Cell Biol 13:713–726. doi: 10.1038/nrm3448 PubMedCrossRefGoogle Scholar
  15. Beltran M et al (2008) A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev 22:756–769. doi: 10.1101/gad.455708 PubMedPubMedCentralCrossRefGoogle Scholar
  16. Berezikov E, Chung WJ, Willis J, Cuppen E, Lai EC (2007) Mammalian mirtron genes. Mol Cell 28:328–336. doi: 10.1016/j.molcel.2007.09.028 PubMedPubMedCentralCrossRefGoogle Scholar
  17. Berger A, Maire S, Gaillard MC, Sahel JA, Hantraye P, Bemelmans AP (2016) mRNA trans-splicing in gene therapy for genetic diseases. Wiley Interdiscip Rev RNA 7:487–498. doi: 10.1002/wrna.1347 PubMedPubMedCentralCrossRefGoogle Scholar
  18. Berglund JA, Chua K, Abovich N, Reed R, Rosbash M (1997) The splicing factor BBP interacts specifically with the pre-mRNA branchpoint sequence UACUAAC. Cell 89:781–787PubMedCrossRefGoogle Scholar
  19. Bergsma AJ, In ‘t Groen SL, Verheijen FW, van der Ploeg AT, Pijnappel WP (2016) From cryptic toward canonical pre-mRNA splicing in pompe disease: a pipeline for the development of antisense oligonucleotides molecular therapy. Nucleic Acids 5:e361. doi: 10.1038/mtna.2016.75 PubMedPubMedCentralCrossRefGoogle Scholar
  20. Berk AJ (2016) Discovery of RNA splicing and genes in pieces. Proc Natl Acad Sci USA 113:801–805. doi: 10.1073/pnas.1525084113 PubMedPubMedCentralCrossRefGoogle Scholar
  21. Beroud C et al (2004) Dystrophinopathy caused by mid-intronic substitutions activating cryptic exons in the DMD gene. Neuromusc Disord NMD 14:10–18PubMedCrossRefGoogle Scholar
  22. Bholah Z, Smith MJ, Byers HJ, Miles EK, Evans DG, Newman WG (2014) Intronic splicing mutations in PTCH1 cause Gorlin syndrome. Fam Cancer 13:477–480. doi: 10.1007/s10689-014-9712-9 PubMedCrossRefGoogle Scholar
  23. Bieberstein NI, Carrillo Oesterreich F, Straube K, Neugebauer KM (2012) First exon length controls active chromatin signatures and transcription. Cell Rep 2:62–68. doi: 10.1016/j.celrep.2012.05.019 PubMedCrossRefGoogle Scholar
  24. Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336. doi: 10.1146/annurev.biochem.72.121801.161720 PubMedCrossRefGoogle Scholar
  25. Blazquez L et al (2013) In vitro correction of a pseudoexon-generating deep intronic mutation in LGMD2A by antisense oligonucleotides and modified small nuclear RNAs. Hum Mutat 34:1387–1395. doi: 10.1002/humu.22379 PubMedCrossRefGoogle Scholar
  26. Bonifert T et al (2014) Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier. Brain J Neurol 137:2164–2177. doi: 10.1093/brain/awu165 CrossRefGoogle Scholar
  27. Bonifert T, Gonzalez Menendez I, Battke F, Theurer Y, Synofzik M, Schols L, Wissinger B (2016) Antisense Oligonucleotide mediated splice correction of a deep intronic mutation in OPA1 molecular therapy. Nucleic Acids 5:e390. doi: 10.1038/mtna.2016.93 PubMedPubMedCentralCrossRefGoogle Scholar
  28. Bortolin ML, Kiss T (1998) Human U19 intron-encoded snoRNA is processed from a long primary transcript that possesses little potential for protein coding. RNA 4:445–454PubMedPubMedCentralGoogle Scholar
  29. Boutz PL, Bhutkar A, Sharp PA (2015) Detained introns are a novel, widespread class of post-transcriptionally spliced introns. Genes Dev 29:63–80. doi: 10.1101/gad.247361.114 PubMedPubMedCentralCrossRefGoogle Scholar
  30. Bovolenta M et al (2008) A novel custom high density-comparative genomic hybridization array detects common rearrangements as well as deep intronic mutations in dystrophinopathies. BMC Genom 9:572. doi: 10.1186/1471-2164-9-572 CrossRefGoogle Scholar
  31. Bovolenta M et al (2010) Identification of a deep intronic mutation in the COL6A2 gene by a novel custom oligonucleotide CGH array designed to explore allelic and genetic heterogeneity in collagen VI-related myopathies. BMC Med Genet 11:44. doi: 10.1186/1471-2350-11-44 PubMedPubMedCentralCrossRefGoogle Scholar
  32. Braun TA et al (2013) Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease. Hum Mol Genet 22:5136–5145. doi: 10.1093/hmg/ddt367 PubMedPubMedCentralCrossRefGoogle Scholar
  33. Brinster RL, Allen JM, Behringer RR, Gelinas RE, Palmiter RD (1988) Introns increase transcriptional efficiency in transgenic mice. Proc Natl Acad Sci USA 85:836–840PubMedPubMedCentralCrossRefGoogle Scholar
  34. Buratti E, Dhir A, Lewandowska MA, Baralle FE (2007) RNA structure is a key regulatory element in pathological ATM and CFTR pseudoexon inclusion events. Nucleic Acids Res 35:4369–4383. doi: 10.1093/nar/gkm447 PubMedPubMedCentralCrossRefGoogle Scholar
  35. Burnette JM, Miyamoto-Sato E, Schaub MA, Conklin J, Lopez AJ (2005) Subdivision of large introns in Drosophila by recursive splicing at nonexonic elements. Genetics 170:661–674. doi: 10.1534/genetics.104.039701 PubMedPubMedCentralCrossRefGoogle Scholar
  36. Busslinger M, Moschonas N, Flavell RA (1981) Beta+ thalassemia: aberrant splicing results from a single point mutation in an intron. Cell 27:289–298PubMedCrossRefGoogle Scholar
  37. Caminsky N, Mucaki EJ, Rogan PK (2014) Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis. F1000Research 3:282. doi: 10.12688/f1000research.5654.1 PubMedPubMedCentralGoogle Scholar
  38. Camtosun E, Siklar Z, Kocaay P, Ceylaner S, Flanagan SE, Ellard S, Berberoglu M (2015) Three cases of Wolfram syndrome with different clinical aspects. J Pediatr Endocrinol Metab JPEM 28:433–438. doi: 10.1515/jpem-2014-0139 PubMedGoogle Scholar
  39. Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285–298. doi: 10.1038/nrg775 PubMedCrossRefGoogle Scholar
  40. Castaman G et al (2011) Deep intronic variations may cause mild hemophilia A. J Thromb Haemost JTH 9:1541–1548. doi: 10.1111/j.1538-7836.2011.04408.x PubMedCrossRefGoogle Scholar
  41. Castellanos E et al (2013) In vitro antisense therapeutics for a deep intronic mutation causing Neurofibromatosis type 2. Eur J Hum Genet EJHG 21:769–773. doi: 10.1038/ejhg.2012.261 PubMedCrossRefGoogle Scholar
  42. Chabot B, Shkreta L (2016) Defective control of pre-messenger RNA splicing in human disease. J Cell Biol 212:13–27. doi: 10.1083/jcb.201510032 PubMedPubMedCentralCrossRefGoogle Scholar
  43. Chen LL (2016) The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol 17:205–211. doi: 10.1038/nrm.2015.32 PubMedCrossRefGoogle Scholar
  44. Chen M, Manley JL (2009) Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 10:741–754. doi: 10.1038/nrm2777 PubMedPubMedCentralGoogle Scholar
  45. Cheng TC et al (1984) beta-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci USA 81:2821–2825PubMedPubMedCentralCrossRefGoogle Scholar
  46. Chillon M et al (1995) A novel donor splice site in intron 11 of the CFTR gene, created by mutation 1811+1.6kbA–>G, produces a new exon: high frequency in Spanish cystic fibrosis chromosomes and association with severe phenotype. Am J Hum Genet 56:623–629PubMedPubMedCentralGoogle Scholar
  47. Chmel N et al (2015) A deep-intronic FERMT1 mutation causes kindler syndrome: an explanation for genetically unsolved cases. J Invest Dermatol 135:2876–2879. doi: 10.1038/jid.2015.227 PubMedCrossRefGoogle Scholar
  48. Chorev M, Carmel L (2013) Computational identification of functional introns: high positional conservation of introns that harbor RNA genes. Nucleic Acids Res 41:5604–5613. doi: 10.1093/nar/gkt244 PubMedPubMedCentralCrossRefGoogle Scholar
  49. Clendenning M et al (2011) Mutation deep within an intron of MSH2 causes Lynch syndrome. Fam Cancer 10:297–301. doi: 10.1007/s10689-011-9427-0 PubMedPubMedCentralCrossRefGoogle Scholar
  50. Corrigan A, Arenas M, Escuredo E, Fairbanks L, Marinaki A (2011) HPRT deficiency: identification of twenty-four novel variants including an unusual deep intronic mutation. Nucleosides Nucleotides Nucleic Acids 30:1260–1265. doi: 10.1080/15257770.2011.590172 PubMedCrossRefGoogle Scholar
  51. Corvelo A, Eyras E (2008) Exon creation and establishment in human genes. Genome Biol 9:R141. doi: 10.1186/gb-2008-9-9-r141 PubMedPubMedCentralCrossRefGoogle Scholar
  52. Costa C et al (2011) A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice. J Cystic Fibros Off J Eur Cystic Fibros Soc 10:479–482. doi: 10.1016/j.jcf.2011.06.011 CrossRefGoogle Scholar
  53. Costantino L et al (2013) Fine characterization of the recurrent c.1584+18672A>G deep-intronic mutation in the cystic fibrosis transmembrane conductance regulator gene. Am J Respir Cell Mol Biol 48:619–625. doi: 10.1165/rcmb.2012-0371OC PubMedCrossRefGoogle Scholar
  54. Coutinho G, Xie J, Du L, Brusco A, Krainer AR, Gatti RA (2005) Functional significance of a deep intronic mutation in the ATM gene and evidence for an alternative exon 28a. Hum Mutat 25:118–124. doi: 10.1002/humu.20170 PubMedCrossRefGoogle Scholar
  55. Cunha KS et al (2016) Hybridization capture-based next-generation sequencing to evaluate coding sequence and deep intronic mutations in the NF1. Gene Genes. doi: 10.3390/genes7120133 PubMedGoogle Scholar
  56. Damgaard CK, Kahns S, Lykke-Andersen S, Nielsen AL, Jensen TH, Kjems J (2008) A 5′ splice site enhances the recruitment of basal transcription initiation factors in vivo. Mol Cell 29:271–278. doi: 10.1016/j.molcel.2007.11.035 PubMedCrossRefGoogle Scholar
  57. David A et al (2007) An intronic growth hormone receptor mutation causing activation of a pseudoexon is associated with a broad spectrum of growth hormone insensitivity phenotypes. J Clin Endocrinol Metab 92:655–659. doi: 10.1210/jc.2006-1527 PubMedCrossRefGoogle Scholar
  58. Davis RL, Homer VM, George PM, Brennan SO (2009) A deep intronic mutation in FGB creates a consensus exonic splicing enhancer motif that results in afibrinogenemia caused by aberrant mRNA splicing, which can be corrected in vitro with antisense oligonucleotide treatment. Hum Mutat 30:221–227. doi: 10.1002/humu.20839 PubMedCrossRefGoogle Scholar
  59. De Klein A et al (1998) A G–>A transition creates a branch point sequence and activation of a cryptic exon, resulting in the hereditary disorder neurofibromatosis 2. Hum Mol Genet 7:393–398PubMedCrossRefGoogle Scholar
  60. Deburgrave N et al (2007) Protein- and mRNA-based phenotype-genotype correlations in DMD/BMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene. Hum Mutat 28:183–195. doi: 10.1002/humu.20422 PubMedCrossRefGoogle Scholar
  61. Dehainault C et al (2007) A deep intronic mutation in the RB1 gene leads to intronic sequence exonisation. Eur J Hum Genet EJHG 15:473–477. doi: 10.1038/sj.ejhg.5201787 PubMedCrossRefGoogle Scholar
  62. den Hollander AI et al (2006) Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet 79:556–561. doi: 10.1086/507318 CrossRefGoogle Scholar
  63. Dhir A, Buratti E (2010) Alternative splicing: role of pseudoexons in human disease and potential therapeutic strategies. FEBS J 277:841–855. doi: 10.1111/j.1742-4658.2009.07520.x PubMedCrossRefGoogle Scholar
  64. Dobkin C, Pergolizzi RG, Bahre P, Bank A (1983) Abnormal splice in a mutant human beta-globin gene not at the site of a mutation. Proc Natl Acad Sci USA 80:1184–1188PubMedPubMedCentralCrossRefGoogle Scholar
  65. Dominov JA, Uyan O, Sapp PC, McKenna-Yasek D, Nallamilli BR, Hegde M, Brown RH Jr (2014) A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides. Ann Clin Transl Neurol 1:703–720. doi: 10.1002/acn3.96 PubMedPubMedCentralCrossRefGoogle Scholar
  66. Dong XY et al (2008) SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer. Hum Mol Genet 17:1031–1042. doi: 10.1093/hmg/ddm375 PubMedPubMedCentralCrossRefGoogle Scholar
  67. Dong XY, Guo P, Boyd J, Sun X, Li Q, Zhou W, Dong JT (2009) Implication of snoRNA U50 in human breast cancer. J Genet Genom 36:447–454. doi: 10.1016/S1673-8527(08)60134-4 CrossRefGoogle Scholar
  68. Dong R, Ma XK, Chen LL, Yang L (2016) Increased complexity of circRNA expression during species evolution. RNA Biol. doi: 10.1080/15476286.2016.1269999 PubMedCentralGoogle Scholar
  69. Dreyfuss G, Kim VN, Kataoka N (2002) Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol 3:195–205. doi: 10.1038/nrm760 PubMedCrossRefGoogle Scholar
  70. Duff MO et al (2015) Genome-wide identification of zero nucleotide recursive splicing in Drosophila. Nature 521:376–379. doi: 10.1038/nature14475 PubMedPubMedCentralCrossRefGoogle Scholar
  71. Edery P et al (2011) Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science 332:240–243. doi: 10.1126/science.1202205 PubMedCrossRefGoogle Scholar
  72. Faa V et al (2009) Characterization of a disease-associated mutation affecting a putative splicing regulatory element in intron 6b of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. J Biol Chem 284:30024–30031. doi: 10.1074/jbc.M109.032623 PubMedPubMedCentralCrossRefGoogle Scholar
  73. Ferlini A, Galie N, Merlini L, Sewry C, Branzi A, Muntoni F (1998) A novel Alu-like element rearranged in the dystrophin gene causes a splicing mutation in a family with X-linked dilated cardiomyopathy. Am J Hum Genet 63:436–446. doi: 10.1086/301952 PubMedPubMedCentralCrossRefGoogle Scholar
  74. Ferri L, Covello G, Caciotti A, Guerrini R, Denti MA, Morrone A (2016) Double-target antisense U1snRNAs correct mis-splicing due to c.639+861C>T and c.639+919G>A GLA deep intronic mutations molecular therapy. Nucleic Acids 5:380. doi:10.1038/mtna.2016.88Google Scholar
  75. Flanagan SE et al (2013) Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation. Am J Hum Genet 92:131–136. doi: 10.1016/j.ajhg.2012.11.017 PubMedPubMedCentralCrossRefGoogle Scholar
  76. Flynt AS, Greimann JC, Chung WJ, Lima CD, Lai EC (2010) MicroRNA biogenesis via splicing and exosome-mediated trimming in Drosophila. Mol Cell 38:900–907. doi: 10.1016/j.molcel.2010.06.014 PubMedPubMedCentralCrossRefGoogle Scholar
  77. Friedman KJ, Kole J, Cohn JA, Knowles MR, Silverman LM, Kole R (1999) Correction of aberrant splicing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by antisense oligonucleotides. J Biol Chem 274:36193–36199PubMedCrossRefGoogle Scholar
  78. Friedrich K et al (2010) WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. Hum Genet 128:103–111. doi: 10.1007/s00439-010-0832-5 PubMedPubMedCentralCrossRefGoogle Scholar
  79. Furniss D, Lettice LA, Taylor IB, Critchley PS, Giele H, Hill RE, Wilkie AO (2008) A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. Hum Mol Genet 17:2417–2423. doi: 10.1093/hmg/ddn141 PubMedPubMedCentralCrossRefGoogle Scholar
  80. Gaffney DJ, Keightley PD (2004) Unexpected conserved non-coding DNA blocks in mammals. Trends Genet TIG 20:332–337. doi: 10.1016/j.tig.2004.06.011 PubMedCrossRefGoogle Scholar
  81. Gallagher RC, Pils B, Albalwi M, Francke U (2002) Evidence for the role of PWCR1/HBII-85 C/D box small nucleolar RNAs in Prader–Willi syndrome. Am J Hum Genet 71:669–678. doi: 10.1086/342408 PubMedPubMedCentralCrossRefGoogle Scholar
  82. Gazzoli I, Pulyakhina I, Verwey NE, Ariyurek Y, Laros JF, t Hoen PA, Aartsma-Rus A (2016) Non-sequential and multi-step splicing of the dystrophin transcript. RNA Biol 13:290–305. doi: 10.1080/15476286.2015.1125074 PubMedCrossRefGoogle Scholar
  83. Gilbert W (1978) Why genes in pieces? Nature 271:501PubMedCrossRefGoogle Scholar
  84. Gilissen C et al (2014) Genome sequencing identifies major causes of severe intellectual disability. Nature 511:344–347. doi: 10.1038/nature13394 PubMedCrossRefGoogle Scholar
  85. Gillis E et al (2014) An FBN1 deep intronic mutation in a familial case of Marfan syndrome: an explanation for genetically unsolved cases? Hum Mutat 35:571–574. doi: 10.1002/humu.22540 PubMedCrossRefGoogle Scholar
  86. Gonorazky H et al (2016) RNAseq analysis for the diagnosis of muscular dystrophy. Ann Clin Transl Neurol 3:55–60. doi: 10.1002/acn3.267 PubMedCrossRefGoogle Scholar
  87. Greer K et al (2015) Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient. Mol Genet Genom Med 3:320–326. doi: 10.1002/mgg3.144 CrossRefGoogle Scholar
  88. Gudipati RK, Xu Z, Lebreton A, Seraphin B, Steinmetz LM, Jacquier A, Libri D (2012) Extensive degradation of RNA precursors by the exosome in wild-type cells. Mol Cell 48:409–421. doi: 10.1016/j.molcel.2012.08.018 PubMedPubMedCentralCrossRefGoogle Scholar
  89. Guo DC, Gupta P, Tran-Fadulu V, Guidry TV, Leduc MS, Schaefer FV, Milewicz DM (2008) An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease. J Hum Genet 53:1007–1011. doi: 10.1007/s10038-008-0334-7 PubMedCrossRefGoogle Scholar
  90. Gurnett CA, Bowcock AM, Dietz FR, Morcuende JA, Murray JC, Dobbs MB (2007) Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly. Am J Med Genet Part A 143A:27–32. doi: 10.1002/ajmg.a.31563 PubMedCrossRefGoogle Scholar
  91. Gurvich OL et al (2008) DMD pseudoexon mutations: splicing efficiency, phenotype, and potential therapy. Ann Neurol 63:81–89. doi: 10.1002/ana.21290 PubMedCrossRefGoogle Scholar
  92. Hall SL, Padgett RA (1996) Requirement of U12 snRNA for in vivo splicing of a minor class of eukaryotic nuclear pre-mRNA introns. Science 271:1716–1718PubMedCrossRefGoogle Scholar
  93. Hang J, Wan R, Yan C, Shi Y (2015) Structural basis of pre-mRNA splicing. Science 349:1191–1198. doi: 10.1126/science.aac8159 PubMedCrossRefGoogle Scholar
  94. Hare MP, Palumbi SR (2003) High intron sequence conservation across three mammalian orders suggests functional constraints. Mol Biol Evol 20:969–978. doi: 10.1093/molbev/msg111 PubMedCrossRefGoogle Scholar
  95. Harland M, Mistry S, Bishop DT, Bishop JA (2001) A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees. Hum Mol Genet 10:2679–2686PubMedCrossRefGoogle Scholar
  96. Hatton AR, Subramaniam V, Lopez AJ (1998) Generation of alternative Ultrabithorax isoforms and stepwise removal of a large intron by resplicing at exon–exon junctions. Mol Cell 2:787–796PubMedCrossRefGoogle Scholar
  97. He H et al (2011) Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science 332:238–240. doi: 10.1126/science.1200587 PubMedPubMedCentralCrossRefGoogle Scholar
  98. Heinzen EL et al (2008) Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol 6:e1. doi: 10.1371/journal.pbio.1000001 PubMedCrossRefGoogle Scholar
  99. Highsmith WE et al (1994) A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 331:974–980. doi: 10.1056/NEJM199410133311503 PubMedCrossRefGoogle Scholar
  100. Hilgert N, Topsakal V, van Dinther J, Offeciers E, Van de Heyning P, Van Camp G (2008) A splice-site mutation and overexpression of MYO6 cause a similar phenotype in two families with autosomal dominant hearing loss. Eur J Hum Genet EJHG 16:593–602. doi: 10.1038/sj.ejhg.5202000 PubMedCrossRefGoogle Scholar
  101. Homolova K, Zavadakova P, Doktor TK, Schroeder LD, Kozich V, Andresen BS (2010) The deep intronic c.903+469T>C mutation in the MTRR gene creates an SF2/ASF binding exonic splicing enhancer, which leads to pseudoexon activation and causes the cblE type of homocystinuria. Hum Mutat 31:437–444. doi: 10.1002/humu.21206 PubMedPubMedCentralCrossRefGoogle Scholar
  102. Hsiao YH, Bahn JH, Lin X, Chan TM, Wang R, Xiao X (2016) Alternative splicing modulated by genetic variants demonstrates accelerated evolution regulated by highly conserved proteins. Genome Res 26:440–450. doi: 10.1101/gr.193359.115 PubMedPubMedCentralCrossRefGoogle Scholar
  103. Hube F, Francastel C (2015) Mammalian introns: when the junk generates molecular diversity. Int J Mol Sci 16:4429–4452. doi: 10.3390/ijms16034429 PubMedPubMedCentralCrossRefGoogle Scholar
  104. Ikeda H et al (1997) Molecular analysis of dihydropteridine reductase deficiency: identification of two novel mutations in Japanese patients. Hum Genet 100:637–642PubMedCrossRefGoogle Scholar
  105. Ikezawa M, Nishino I, Goto Y, Miike T, Nonaka I (1999) Newly recognized exons induced by a splicing abnormality from an intronic mutation of the dystrophin gene resulting in Duchenne muscular dystrophy. Mutations in brief no. 213. Online. Hum Mutat 13:170. doi: 10.1002/(SICI)1098-1004(1999)13:2<170:AID-HUMU12>3.0.CO;2-7 PubMedCrossRefGoogle Scholar
  106. Inaba H, Koyama T, Shinozawa K, Amano K, Fukutake K (2013) Identification and characterization of an adenine to guanine transition within intron 10 of the factor VIII gene as a causative mutation in a patient with mild haemophilia A. Haemoph Off J World Feder Hemoph 19:100–105. doi: 10.1111/j.1365-2516.2012.02906.x CrossRefGoogle Scholar
  107. Irimia M, Roy SW (2014) Origin of spliceosomal introns and alternative splicing. Cold Spring Harbor Perspect Biol. doi: 10.1101/cshperspect.a016071 Google Scholar
  108. Ishii S, Nakao S, Minamikawa-Tachino R, Desnick RJ, Fan JQ (2002) Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype. Am J Hum Genet 70:994–1002. doi: 10.1086/339431 PubMedPubMedCentralCrossRefGoogle Scholar
  109. Jafarifar F, Dietrich RC, Hiznay JM, Padgett RA (2014) Biochemical defects in minor spliceosome function in the developmental disorder MOPD I. RNA 20:1078–1089. doi: 10.1261/rna.045187.114 PubMedPubMedCentralCrossRefGoogle Scholar
  110. Jaillon O et al (2008) Translational control of intron splicing in eukaryotes. Nature 451:359–362. doi: 10.1038/nature06495 PubMedCrossRefGoogle Scholar
  111. Janz S, Potter M, Rabkin CS (2003) Lymphoma- and leukemia-associated chromosomal translocations in healthy individuals. Genes Chromosom Cancer 36:211–223. doi: 10.1002/gcc.10178 PubMedCrossRefGoogle Scholar
  112. Jeck WR et al (2013) Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19:141–157. doi: 10.1261/rna.035667.112 PubMedPubMedCentralCrossRefGoogle Scholar
  113. Juneau K, Miranda M, Hillenmeyer ME, Nislow C, Davis RW (2006) Introns regulate RNA and protein abundance in yeast. Genetics 174:511–518. doi: 10.1534/genetics.106.058560 PubMedPubMedCentralCrossRefGoogle Scholar
  114. Kaida D, Berg MG, Younis I, Kasim M, Singh LN, Wan L, Dreyfuss G (2010) U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468:664–668. doi: 10.1038/nature09479 PubMedPubMedCentralCrossRefGoogle Scholar
  115. Kansakoski J et al (2016) Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene. Sci Rep 6:32819. doi: 10.1038/srep32819 PubMedPubMedCentralCrossRefGoogle Scholar
  116. Kelly S et al (2015) Splicing of many human genes involves sites embedded within introns. Nucleic Acids Res 43:4721–4732. doi: 10.1093/nar/gkv386 PubMedPubMedCentralCrossRefGoogle Scholar
  117. Keren H, Lev-Maor G, Ast G (2010) Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 11:345–355. doi: 10.1038/nrg2776 PubMedCrossRefGoogle Scholar
  118. Khelifi MM et al (2011) Pure intronic rearrangements leading to aberrant pseudoexon inclusion in dystrophinopathy: a new class of mutations? Hum Mutat 32:467–475. doi: 10.1002/humu.21471 PubMedCrossRefGoogle Scholar
  119. King K, Flinter FA, Nihalani V, Green PM (2002) Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome. Hum Genet 111:548–554. doi: 10.1007/s00439-002-0830-3 PubMedCrossRefGoogle Scholar
  120. Knebelmann B et al (1995) Splice-mediated insertion of an Alu sequence in the COL4A3 mRNA causing autosomal recessive Alport syndrome. Hum Mol Genet 4:675–679PubMedCrossRefGoogle Scholar
  121. Kollberg G et al (2009) Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy. Brain J Neurol 132:2170–2179. doi: 10.1093/brain/awp152 CrossRefGoogle Scholar
  122. Konarska MM, Padgett RA, Sharp PA (1985) Trans splicing of mRNA precursors in vitro. Cell 42:165–171PubMedCrossRefGoogle Scholar
  123. Krawczak M, Thomas NS, Hundrieser B, Mort M, Wittig M, Hampe J, Cooper DN (2007) Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicing. Hum Mutat 28:150–158. doi: 10.1002/humu.20400 PubMedCrossRefGoogle Scholar
  124. Kurio H, Murayama E, Kaneko T, Shibata Y, Inai T, Iida H (2008) Intron retention generates a novel isoform of CEACAM6 that may act as an adhesion molecule in the ectoplasmic specialization structures between spermatids and sertoli cells in rat testis. Biol Reprod 79:1062–1073. doi: 10.1095/biolreprod.108.069872 PubMedCrossRefGoogle Scholar
  125. Kwek KY et al (2002) U1 snRNA associates with TFIIH and regulates transcriptional initiation. Nat Struct Biol 9:800–805. doi: 10.1038/nsb862 PubMedGoogle Scholar
  126. Lebon S et al (2007) A novel mutation of the NDUFS7 gene leads to activation of a cryptic exon and impaired assembly of mitochondrial complex I in a patient with Leigh syndrome. Mol Genet Metab 92:104–108. doi: 10.1016/j.ymgme.2007.05.010 PubMedCrossRefGoogle Scholar
  127. Lee WI, Torgerson TR, Schumacher MJ, Yel L, Zhu Q, Ochs HD (2005) Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. Blood 105:1881–1890. doi: 10.1182/blood-2003-12-4420 PubMedCrossRefGoogle Scholar
  128. Lettice LA et al (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 12:1725–1735PubMedCrossRefGoogle Scholar
  129. Li H, Wang J, Mor G, Sklar J (2008) A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells. Science 321:1357–1361. doi: 10.1126/science.1156725 PubMedCrossRefGoogle Scholar
  130. Liang D, Wilusz JE (2014) Short intronic repeat sequences facilitate circular RNA production. Genes Develop 28:2233–2247. doi: 10.1101/gad.251926.114 PubMedPubMedCentralCrossRefGoogle Scholar
  131. Liquori A et al (2016) Whole USH2A gene sequencing identifies several new deep intronic mutations. Hum Mutat 37:184–193. doi: 10.1002/humu.22926 PubMedCrossRefGoogle Scholar
  132. Liu HX, Zhang M, Krainer AR (1998) Identification of functional exonic splicing enhancer motifs recognized by individual SR proteins. Genes Dev 12:1998–2012PubMedPubMedCentralCrossRefGoogle Scholar
  133. Liu Z et al (2001) Structural basis for recognition of the intron branch site RNA by splicing factor 1. Science 294:1098–1102. doi: 10.1126/science.1064719 PubMedCrossRefGoogle Scholar
  134. Lo YF et al (2011) Recurrent deep intronic mutations in the SLC12A3 gene responsible for Gitelman’s syndrome. Clin J Am Soc Nephrol CJASN 6:630–639. doi: 10.2215/CJN.06730810 PubMedCrossRefGoogle Scholar
  135. Long M, Betran E, Thornton K, Wang W (2003) The origin of new genes: glimpses from the young and old. Nat Rev Genet 4:865–875. doi: 10.1038/nrg1204 PubMedCrossRefGoogle Scholar
  136. Lopez-Bigas N, Audit B, Ouzounis C, Parra G, Guigo R (2005) Are splicing mutations the most frequent cause of hereditary disease? FEBS Lett 579:1900–1903. doi: 10.1016/j.febslet.2005.02.047 PubMedCrossRefGoogle Scholar
  137. Madden HR, Fletcher S, Davis MR, Wilton SD (2009) Characterization of a complex Duchenne muscular dystrophy-causing dystrophin gene inversion and restoration of the reading frame by induced exon skipping. Hum Mutat 30:22–28. doi: 10.1002/humu.20806 PubMedCrossRefGoogle Scholar
  138. Mancini C et al (2012) Megalencephalic leukoencephalopathy with subcortical cysts type 1 (MLC1) due to a homozygous deep intronic splicing mutation (c.895-226T>G) abrogated in vitro using an antisense morpholino oligonucleotide. Neurogenetics 13:205–214. doi: 10.1007/s10048-012-0331-z PubMedCrossRefGoogle Scholar
  139. Masala MV et al (2007) Epidemiology and clinical aspects of Werner’s syndrome in North Sardinia: description of a cluster. Eur J Dermatol EJD 17:213–216. doi: 10.1684/ejd.2007.0155 PubMedGoogle Scholar
  140. Mattick JS (2001) Non-coding RNAs: the architects of eukaryotic complexity. EMBO Rep 2:986–991. doi: 10.1093/embo-reports/kve230 PubMedPubMedCentralCrossRefGoogle Scholar
  141. Mattick JS, Gagen MJ (2001) The evolution of controlled multitasked gene networks: the role of introns and other noncoding RNAs in the development of complex organisms. Mol Biol Evol 18:1611–1630PubMedCrossRefGoogle Scholar
  142. Mauger O, Lemoine F, Scheiffele P (2016) Targeted intron retention and excision for rapid gene regulation in response to neuronal activity. Neuron 92:1266–1278. doi: 10.1016/j.neuron.2016.11.032 PubMedCrossRefGoogle Scholar
  143. Maxwell ES, Fournier MJ (1995) The small nucleolar RNAs. Annu Rev Biochem 64:897–934. doi: 10.1146/annurev.bi.64.070195.004341 PubMedCrossRefGoogle Scholar
  144. Mayer K, Ballhausen W, Leistner W, Rott H (2000) Three novel types of splicing aberrations in the tuberous sclerosis TSC2 gene caused by mutations apart from splice consensus sequences. Biochem Biophys Acta 1502:495–507PubMedGoogle Scholar
  145. McConville CM, Stankovic T, Byrd PJ, McGuire GM, Yao QY, Lennox GG, Taylor MR (1996) Mutations associated with variant phenotypes in ataxia-telangiectasia. Am J Hum Genet 59:320–330PubMedPubMedCentralGoogle Scholar
  146. McKenzie RW, Brennan MD (1996) The two small introns of the Drosophila affinidisjuncta Adh gene are required for normal transcription. Nucleic Acids Res 24:3635–3642PubMedPubMedCentralCrossRefGoogle Scholar
  147. Merendino L, Guth S, Bilbao D, Martinez C, Valcarcel J (1999) Inhibition of msl-2 splicing by Sex-lethal reveals interaction between U2AF35 and the 3′ splice site AG. Nature 402:838–841. doi: 10.1038/45602 PubMedCrossRefGoogle Scholar
  148. Merico D et al (2015) Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. Nature Commun 6:8718. doi: 10.1038/ncomms9718 CrossRefGoogle Scholar
  149. Mertens F, Johansson B, Fioretos T, Mitelman F (2015) The emerging complexity of gene fusions in cancer. Nat Rev Cancer 15:371–381. doi: 10.1038/nrc3947 PubMedCrossRefGoogle Scholar
  150. Metherell LA et al (2001) Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity. Am J Hum Genet 69:641–646. doi: 10.1086/323266 PubMedPubMedCentralCrossRefGoogle Scholar
  151. Michel-Calemard L et al (2009) Pseudoexon activation in the PKHD1 gene: a French founder intronic mutation IVS46+653A>G causing severe autosomal recessive polycystic kidney disease. Clin Genet 75:203–206. doi: 10.1111/j.1399-0004.2008.01106.x PubMedCrossRefGoogle Scholar
  152. Mitchell GA et al (1991) Splice-mediated insertion of an Alu sequence inactivates ornithine delta-aminotransferase: a role for Alu elements in human mutation. Proc Natl Acad Sci USA 88:815–819PubMedPubMedCentralCrossRefGoogle Scholar
  153. Mochel F et al (2008) Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. Am J Hum Genet 82:652–660. doi: 10.1016/j.ajhg.2007.12.012 PubMedPubMedCentralCrossRefGoogle Scholar
  154. Monnier N, Gout JP, Pin I, Gauthier G, Lunardi J (2001) A novel 3600+11.5 kb C>G homozygous splicing mutation in a black African, consanguineous CF family. J Med Genet 38:E4PubMedPubMedCentralCrossRefGoogle Scholar
  155. Monnier N, Ferreiro A, Marty I, Labarre-Vila A, Mezin P, Lunardi J (2003) A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum Mol Genet 12:1171–1178PubMedCrossRefGoogle Scholar
  156. Naftelberg S, Schor IE, Ast G, Kornblihtt AR (2015) Regulation of alternative splicing through coupling with transcription and chromatin structure. Annu Rev Biochem 84:165–198. doi: 10.1146/annurev-biochem-060614-034242 PubMedCrossRefGoogle Scholar
  157. Naro C et al (2017) An orchestrated intron retention program in meiosis controls timely usage of transcripts during germ cell differentiation. Dev Cell 41(82–93):e84. doi: 10.1016/j.devcel.2017.03.003 Google Scholar
  158. Naruto T, Okamoto N, Masuda K, Endo T, Hatsukawa Y, Kohmoto T, Imoto I (2015) Deep intronic GPR143 mutation in a Japanese family with ocular albinism. Sci Rep 5:11334. doi: 10.1038/srep11334 PubMedPubMedCentralCrossRefGoogle Scholar
  159. Nathan N, Girodon E, Clement A, Corvol H (2012) A rare CFTR intronic mutation related to a mild CF disease in a 12-year-old girl. BMJ Case Rep. doi: 10.1136/bcr-2012-006918 PubMedPubMedCentralGoogle Scholar
  160. Noack D, Heyworth PG, Newburger PE, Cross AR (2001) An unusual intronic mutation in the CYBB gene giving rise to chronic granulomatous disease. Biochem Biophys Acta 1537:125–131PubMedGoogle Scholar
  161. Nozu K et al (2009) A deep intronic mutation in the SLC12A3 gene leads to Gitelman syndrome. Pediatr Res 66:590–593. doi: 10.1203/PDR.0b013e3181b9b4d3 PubMedCrossRefGoogle Scholar
  162. Ogino W et al (2007) Mutation analysis of the ornithine transcarbamylase (OTC) gene in five Japanese OTC deficiency patients revealed two known and three novel mutations including a deep intronic mutation. Kobe J Med Sci 53:229–240PubMedGoogle Scholar
  163. Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC (2007) The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130:89–100. doi: 10.1016/j.cell.2007.06.028 PubMedPubMedCentralCrossRefGoogle Scholar
  164. Olsson A, Lind L, Thornell LE, Holmberg M (2008) Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. Hum Mol Genet 17:1666–1672. doi: 10.1093/hmg/ddn057 PubMedCrossRefGoogle Scholar
  165. Padgett RA (2012) New connections between splicing and human disease. Trends Genet TIG 28:147–154. doi: 10.1016/j.tig.2012.01.001 PubMedCrossRefGoogle Scholar
  166. Pagani F, Buratti E, Stuani C, Bendix R, Dork T, Baralle FE (2002) A new type of mutation causes a splicing defect in ATM. Nat Genet 30:426–429. doi: 10.1038/ng858 PubMedCrossRefGoogle Scholar
  167. Palagano E et al (2015) Buried in the Middle but guilty: intronic mutations in the TCIRG1 gene cause human autosomal recessive osteopetrosis. J Bone Miner Res Off J Am Soc Bone Miner Res 30:1814–1821. doi: 10.1002/jbmr.2517 CrossRefGoogle Scholar
  168. Palhais B, Dembic M, Sabaratnam R, Nielsen KS, Doktor TK, Bruun GH, Andresen BS (2016) The prevalent deep intronic c. 639+919 G>A GLA mutation causes pseudoexon activation and Fabry disease by abolishing the binding of hnRNPA1 and hnRNP A2/B1 to a splicing silencer. Mol Genet Metab 119:258–269. doi: 10.1016/j.ymgme.2016.08.007 PubMedCrossRefGoogle Scholar
  169. Papasaikas P, Valcarcel J (2016) The spliceosome: the ultimate RNA chaperone and sculptor. Trends Biochem Sci 41:33–45. doi: 10.1016/j.tibs.2015.11.003 PubMedCrossRefGoogle Scholar
  170. Park SG, Hannenhalli S, Choi SS (2014) Conservation in first introns is positively associated with the number of exons within genes and the presence of regulatory epigenetic signals. BMC Genom 15:526. doi: 10.1186/1471-2164-15-526 CrossRefGoogle Scholar
  171. Patel AA, Steitz JA (2003) Splicing double: insights from the second spliceosome. Nat Rev Mol Cell Biol 4:960–970. doi: 10.1038/nrm1259 PubMedCrossRefGoogle Scholar
  172. Pedrotti S, Cooper TA (2014) In Brief: (mis)splicing in disease. J Pathol 233:1–3. doi: 10.1002/path.4337 PubMedPubMedCentralCrossRefGoogle Scholar
  173. Pezeshkpoor B et al (2013) Deep intronic ‘mutations’ cause hemophilia A: application of next generation sequencing in patients without detectable mutation in F8 cDNA. J Thromb Haemost JTH 11:1679–1687. doi: 10.1111/jth.12339 PubMedCrossRefGoogle Scholar
  174. Pickrell JK, Pai AA, Gilad Y, Pritchard JK (2010) Noisy splicing drives mRNA isoform diversity in human cells. PLoS Genet 6:e1001236. doi: 10.1371/journal.pgen.1001236 PubMedPubMedCentralCrossRefGoogle Scholar
  175. Plate M, Duga S, Castaman G, Rodeghiero F, Asselta R (2009) Recurrence of the ‘deep-intronic’ FGG IVS6-320A>T mutation causing quantitative fibrinogen deficiency in the Italian population of Veneto. Blood Coagul Fibrinolysis Int J Haemost Thromb 20:381–384CrossRefGoogle Scholar
  176. Popp MW, Maquat LE (2013) Organizing principles of mammalian nonsense-mediated mRNA decay. Annu Rev Genet 47:139–165. doi: 10.1146/annurev-genet-111212-133424 PubMedPubMedCentralCrossRefGoogle Scholar
  177. Purevsuren J, Fukao T, Hasegawa Y, Fukuda S, Kobayashi H, Yamaguchi S (2008) Study of deep intronic sequence exonization in a Japanese neonate with a mitochondrial trifunctional protein deficiency. Mol Genet Metab 95:46–51. doi: 10.1016/j.ymgme.2008.06.013 PubMedCrossRefGoogle Scholar
  178. Puttaraju M, Jamison SF, Mansfield SG, Garcia-Blanco MA, Mitchell LG (1999) Spliceosome-mediated RNA trans-splicing as a tool for gene therapy. Nat Biotechnol 17:246–252. doi: 10.1038/6986 PubMedCrossRefGoogle Scholar
  179. Rathmann M, Bunge S, Beck M, Kresse H, Tylki-Szymanska A, Gal A (1996) Mucopolysaccharidosis type II (Hunter syndrome): mutation “hot spots” in the iduronate-2-sulfatase gene. Am J Hum Genet 59:1202–1209PubMedPubMedCentralGoogle Scholar
  180. Richards AJ, McNinch A, Whittaker J, Treacy B, Oakhill K, Poulson A, Snead MP (2012) Splicing analysis of unclassified variants in COL2A1 and COL11A1 identifies deep intronic pathogenic mutations. Eur J Hum Genet 20:552–558. doi: 10.1038/ejhg.2011.223 PubMedCrossRefGoogle Scholar
  181. Rickman DS et al (2009) SLC45A3-ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer. Can Res 69:2734–2738. doi: 10.1158/0008-5472.CAN-08-4926 CrossRefGoogle Scholar
  182. Rincon A, Aguado C, Desviat LR, Sanchez-Alcudia R, Ugarte M, Perez B (2007) Propionic and methylmalonic acidemia: antisense therapeutics for intronic variations causing aberrantly spliced messenger RNA. Am J Hum Genet 81:1262–1270. doi: 10.1086/522376 PubMedPubMedCentralCrossRefGoogle Scholar
  183. Rio Frio T, McGee TL, Wade NM, Iseli C, Beckmann JS, Berson EL, Rivolta C (2009) A single-base substitution within an intronic repetitive element causes dominant retinitis pigmentosa with reduced penetrance. Hum Mutat 30:1340–1347. doi: 10.1002/humu.21071 PubMedPubMedCentralCrossRefGoogle Scholar
  184. Roca X, Sachidanandam R, Krainer AR (2003) Intrinsic differences between authentic and cryptic 5′ splice sites. Nucleic Acids Res 31:6321–6333PubMedPubMedCentralCrossRefGoogle Scholar
  185. Roca X, Akerman M, Gaus H, Berdeja A, Bennett CF, Krainer AR (2012) Widespread recognition of 5′ splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides. Genes Dev 26:1098–1109. doi: 10.1101/gad.190173.112 PubMedPubMedCentralCrossRefGoogle Scholar
  186. Roca X, Krainer AR, Eperon IC (2013) Pick one, but be quick: 5′ splice sites and the problems of too many choices. Genes Dev 27:129–144. doi: 10.1101/gad.209759.112 PubMedPubMedCentralCrossRefGoogle Scholar
  187. Rodriguez-Pascau L, Coll MJ, Vilageliu L, Grinberg D (2009) Antisense oligonucleotide treatment for a pseudoexon-generating mutation in the NPC1 gene causing Niemann-Pick type C disease. Hum Mutat 30:E993–E1001. doi: 10.1002/humu.21119 PubMedCrossRefGoogle Scholar
  188. Rogozin IB, Wolf YI, Sorokin AV, Mirkin BG, Koonin EV (2003) Remarkable interkingdom conservation of intron positions and massive, lineage-specific intron loss and gain in eukaryotic evolution. Curr Biol 13:1512–1517PubMedCrossRefGoogle Scholar
  189. Romano M, Buratti E, Baralle D (2013) Role of pseudoexons and pseudointrons in human cancer. Int J Cell Biol 2013:810572. doi: 10.1155/2013/810572 PubMedPubMedCentralCrossRefGoogle Scholar
  190. Roy SW, Irimia M (2008) Intron mis-splicing: no alternative? Genome Biol 9:208. doi: 10.1186/gb-2008-9-2-208 PubMedPubMedCentralCrossRefGoogle Scholar
  191. Ruan GX, Barry E, Yu D, Lukason M, Cheng SH, Scaria A (2017) CRISPR/Cas9-mediated genome editing as a therapeutic approach for leber congenital amaurosis 10. Mol Ther J Am Soc Gene Ther 25:331–341. doi: 10.1016/j.ymthe.2016.12.006 CrossRefGoogle Scholar
  192. Rump A et al (2006) A splice-supporting intronic mutation in the last bp position of a cryptic exon within intron 6 of the CYBB gene induces its incorporation into the mRNA causing chronic granulomatous disease (CGD). Gene 371:174–181. doi: 10.1016/j.gene.2005.11.036 PubMedCrossRefGoogle Scholar
  193. Runte M, Huttenhofer A, Gross S, Kiefmann M, Horsthemke B, Buiting K (2001) The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum Mol Genet 10:2687–2700PubMedCrossRefGoogle Scholar
  194. Ruskin B, Green MR (1985) An RNA processing activity that debranches RNA lariats. Science 229:135–140PubMedCrossRefGoogle Scholar
  195. Sagai T, Hosoya M, Mizushina Y, Tamura M, Shiroishi T (2005) Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb. Development 132:797–803. doi: 10.1242/dev.01613 PubMedCrossRefGoogle Scholar
  196. Sahoo T et al (2008) Prader–Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet 40:719–721. doi: 10.1038/ng.158 PubMedPubMedCentralCrossRefGoogle Scholar
  197. Sakamoto O, Ohura T, Katsushima Y, Fujiwara I, Ogawa E, Miyabayashi S, Iinuma K (2001) A novel intronic mutation of the TAZ (G4.5) gene in a patient with Barth syndrome: creation of a 5′ splice donor site with variant GC consensus and elongation of the upstream exon. Hum Genet 109:559–563. doi: 10.1007/s00439-001-0612-3 PubMedCrossRefGoogle Scholar
  198. Salzman J (2016) Circular RNA expression: its potential regulation and function trends in genetics. TIG 32:309–316. doi: 10.1016/j.tig.2016.03.002 PubMedPubMedCentralCrossRefGoogle Scholar
  199. Schlackow M, Nojima T, Gomes T, Dhir A, Carmo-Fonseca M, Proudfoot NJ (2017) Distinctive patterns of transcription and RNA processing for human lincRNAs. Mol Cell 65:25–38. doi: 10.1016/j.molcel.2016.11.029 PubMedPubMedCentralCrossRefGoogle Scholar
  200. Schneider A, Maas SM, Hennekam RC, Hanauer A (2013) Identification of the first deep intronic mutation in the RPS6KA3 gene in a patient with a severe form of Coffin-Lowry syndrome. Eur J Med Genet 56:150–152. doi: 10.1016/j.ejmg.2012.11.007 PubMedCrossRefGoogle Scholar
  201. Schollen E et al (2007) Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients. Mol Genet Metab 90:408–413. doi: 10.1016/j.ymgme.2007.01.003 PubMedCrossRefGoogle Scholar
  202. Schulz HL et al (2017) Mutation spectrum of the ABCA4 gene in 335 stargardt disease patients from a multicenter german cohort-impact of selected deep intronic variants and common SNPs. Invest Ophthalmol Vis Sci 58:394–403. doi: 10.1167/iovs.16-19936 PubMedPubMedCentralCrossRefGoogle Scholar
  203. Scotti MM, Swanson MS (2016) RNA mis-splicing in disease. Nat Rev Genet 17:19–32. doi: 10.1038/nrg.2015.3 PubMedCrossRefGoogle Scholar
  204. Seraphin B, Rosbash M (1989) Identification of functional U1 snRNA-pre-mRNA complexes committed to spliceosome assembly and splicing. Cell 59:349–358PubMedCrossRefGoogle Scholar
  205. Shabalina SA, Ogurtsov AY, Spiridonov AN, Novichkov PS, Spiridonov NA, Koonin EV (2010) Distinct patterns of expression and evolution of intronless and intron-containing mammalian genes. Mol Biol Evol 27:1745–1749. doi: 10.1093/molbev/msq086 PubMedPubMedCentralCrossRefGoogle Scholar
  206. Sharp PA, Konarksa MM, Grabowski PJ, Lamond AI, Marciniak R, Seiler SR (1987) Splicing of messenger RNA precursors. Cold Spring Harb Symp Quant Biol 52:277–285PubMedCrossRefGoogle Scholar
  207. Sibley CR et al (2015) Recursive splicing in long vertebrate genes. Nature 521:371–375. doi: 10.1038/nature14466 PubMedPubMedCentralCrossRefGoogle Scholar
  208. Sibley CR, Blazquez L, Ule J (2016) Lessons from non-canonical splicing. Nat Rev Genet 17:407–421. doi: 10.1038/nrg.2016.46 PubMedPubMedCentralCrossRefGoogle Scholar
  209. Singh RK, Cooper TA (2012) Pre-mRNA splicing in disease and therapeutics. Trends Mol Med 18:472–482. doi: 10.1016/j.molmed.2012.06.006 PubMedPubMedCentralCrossRefGoogle Scholar
  210. Siprashvili Z et al (2016) The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer. Nat Genet 48:53–58. doi: 10.1038/ng.3452 PubMedCrossRefGoogle Scholar
  211. Sironi M et al (2004) Silencer elements as possible inhibitors of pseudoexon splicing. Nucleic Acids Res 32:1783–1791. doi: 10.1093/nar/gkh341 PubMedPubMedCentralCrossRefGoogle Scholar
  212. Solnick D (1985) Trans splicing of mRNA precursors. Cell 42:157–164PubMedCrossRefGoogle Scholar
  213. Spena S, Asselta R, Plate M, Castaman G, Duga S, Tenchini ML (2007) Pseudo-exon activation caused by a deep-intronic mutation in the fibrinogen gamma-chain gene as a novel mechanism for congenital afibrinogenaemia. Br J Haematol 139:128–132. doi: 10.1111/j.1365-2141.2007.06758.x PubMedCrossRefGoogle Scholar
  214. Spier I et al (2012) Deep intronic APC mutations explain a substantial proportion of patients with familial or early-onset adenomatous polyposis. Hum Mutat 33:1045–1050. doi: 10.1002/humu.22082 PubMedCrossRefGoogle Scholar
  215. Spritz RA et al (1981) Base substitution in an intervening sequence of a beta+-thalassemic human globin gene. Proc Natl Acad Sci USA 78:2455–2459PubMedPubMedCentralCrossRefGoogle Scholar
  216. Stadhouders R, van den Heuvel A, Kolovos P, Jorna R, Leslie K, Grosveld F, Soler E (2012) Transcription regulation by distal enhancers: who’s in the loop? Transcription 3:181–186. doi: 10.4161/trns.20720 PubMedPubMedCentralCrossRefGoogle Scholar
  217. Stenson PD, Ball EV, Mort M, Phillips AD, Shaw K, Cooper DN (2012) The Human Gene Mutation Database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protoc Bioinf Chapter 1(Unit1):13. doi: 10.1002/0471250953.bi0113s39 Google Scholar
  218. Sterne-Weiler T, Sanford JR (2014) Exon identity crisis: disease-causing mutations that disrupt the splicing code. Genome Biol 15:201. doi: 10.1186/gb4150 PubMedPubMedCentralCrossRefGoogle Scholar
  219. Sterne-Weiler T, Howard J, Mort M, Cooper DN, Sanford JR (2011) Loss of exon identity is a common mechanism of human inherited disease. Genome Res 21:1563–1571. doi: 10.1101/gr.118638.110 PubMedPubMedCentralCrossRefGoogle Scholar
  220. Straniero L et al (2016) Whole-gene CFTR sequencing combined with digital RT-PCR improves genetic diagnosis of cystic fibrosis. J Hum Genet 61:977–984. doi: 10.1038/jhg.2016.101 PubMedCrossRefGoogle Scholar
  221. Stum M et al (2006) Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz–Jampel syndrome. Hum Mutat 27:1082–1091. doi: 10.1002/humu.20388 PubMedCrossRefGoogle Scholar
  222. Svaasand EK, Engebretsen LF, Ludvigsen T, Brechan W, Sjursen W (2015) A novel deep intronic mutation introducing a cryptic exon causing neurofibromatosis type 1 in a family with highly variable phenotypes: a case study 4. doi: 10.4172/2161-1041.1000152
  223. Szafranski P, Yang Y, Nelson MU, Bizzarro MJ, Morotti RA, Langston C, Stankiewicz P (2013) Novel FOXF1 deep intronic deletion causes lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins. Hum Mutat 34:1467–1471. doi: 10.1002/humu.22395 PubMedPubMedCentralCrossRefGoogle Scholar
  224. Takeshima Y et al (2010) Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center. J Hum Genet 55:379–388. doi: 10.1038/jhg.2010.49 PubMedCrossRefGoogle Scholar
  225. Tarn WY, Steitz JA (1996a) Highly diverged U4 and U6 small nuclear RNAs required for splicing rare AT–AC introns. Science 273:1824–1832PubMedCrossRefGoogle Scholar
  226. Tarn WY, Steitz JA (1996b) A novel spliceosome containing U11, U12, and U5 snRNPs excises a minor class (AT–AC) intron in vitro. Cell 84:801–811PubMedCrossRefGoogle Scholar
  227. Trabelsi M, Beugnet C, Deburgrave N, Commere V, Orhant L, Leturcq F, Chelly J (2014) When a mid-intronic variation of DMD gene creates an ESE site. Neuromusc Disord 24:1111–1117. doi: 10.1016/j.nmd.2014.07.003 PubMedCrossRefGoogle Scholar
  228. Treisman R, Orkin SH, Maniatis T (1983) Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature 302:591–596PubMedCrossRefGoogle Scholar
  229. Tsunemoto RK, Eade KT, Blanchard JW, Baldwin KK (2015) Forward engineering neuronal diversity using direct reprogramming. EMBO J 34:1445–1455. doi: 10.15252/embj.201591402 PubMedPubMedCentralCrossRefGoogle Scholar
  230. Tsuruta M et al (1998) Molecular basis of intermittent maple syrup urine disease: novel mutations in the E2 gene of the branched-chain alpha-keto acid dehydrogenase complex. J Hum Genet 43:91–100. doi: 10.1007/s100380050047 PubMedCrossRefGoogle Scholar
  231. Tuffery-Giraud S, Saquet C, Chambert S, Claustres M (2003) Pseudoexon activation in the DMD gene as a novel mechanism for Becker muscular dystrophy. Hum Mutat 21:608–614. doi: 10.1002/humu.10214 PubMedCrossRefGoogle Scholar
  232. Tycowski KT, Shu MD, Steitz JA (1996) A mammalian gene with introns instead of exons generating stable RNA products. Nature 379:464–466. doi: 10.1038/379464a0 PubMedCrossRefGoogle Scholar
  233. Valdmanis PN et al (2009) A mutation that creates a pseudoexon in SOD1 causes familial ALS. Ann Hum Genet 73:652–657PubMedCrossRefGoogle Scholar
  234. Valen E et al (2011) Biogenic mechanisms and utilization of small RNAs derived from human protein-coding genes. Nat Struct Mol Biol 18:1075–1082. doi: 10.1038/nsmb.2091 PubMedCrossRefGoogle Scholar
  235. van den Hurk JA et al (2003) Novel types of mutation in the choroideremia (CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon. Hum Genet 113:268–275. doi: 10.1007/s00439-003-0970-0 PubMedCrossRefGoogle Scholar
  236. van Kuilenburg AB et al (2010) Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity. Hum Genet 128:529–538. doi: 10.1007/s00439-010-0879-3 PubMedPubMedCentralCrossRefGoogle Scholar
  237. Varon R et al (2003) Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome. Nat Genet 35:185–189. doi: 10.1038/ng1243 PubMedCrossRefGoogle Scholar
  238. Vega AI, Perez-Cerda C, Desviat LR, Matthijs G, Ugarte M, Perez B (2009) Functional analysis of three splicing mutations identified in the PMM2 gene: toward a new therapy for congenital disorder of glycosylation type Ia. Hum Mutat 30:795–803. doi: 10.1002/humu.20960 PubMedCrossRefGoogle Scholar
  239. Vervoort R, Gitzelmann R, Lissens W, Liebaers I (1998) A mutation (IVS8+0.6kbdelTC) creating a new donor splice site activates a cryptic exon in an Alu-element in intron 8 of the human beta-glucuronidase gene. Hum Genet 103:686–693PubMedGoogle Scholar
  240. Vetrini F et al (2006) Aberrant splicing in the ocular albinism type 1 gene (OA1/GPR143) is corrected in vitro by morpholino antisense oligonucleotides. Hum Mutat 27:420–426. doi: 10.1002/humu.20303 PubMedCrossRefGoogle Scholar
  241. Vorechovsky I (2010) Transposable elements in disease-associated cryptic exons. Hum Genet 127:135–154. doi: 10.1007/s00439-009-0752-4 PubMedCrossRefGoogle Scholar
  242. Wahl MC, Will CL, Luhrmann R (2009) The spliceosome: design principles of a dynamic RNP machine. Cell 136:701–718. doi: 10.1016/j.cell.2009.02.009 PubMedCrossRefGoogle Scholar
  243. Walenkamp MJ et al (2013) Genetic analysis of GHR should contain sequencing of all coding exons and specific intron sequences, and screening for exon deletions. Hormone Res Paediatr 80:406–412. doi: 10.1159/000355928 CrossRefGoogle Scholar
  244. Wang Z, Burge CB (2008) Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 14:802–813. doi: 10.1261/rna.876308 PubMedPubMedCentralCrossRefGoogle Scholar
  245. Wang GS, Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8:749–761. doi: 10.1038/nrg2164 PubMedCrossRefGoogle Scholar
  246. Wang Z, Rolish ME, Yeo G, Tung V, Mawson M, Burge CB (2004) Systematic identification and analysis of exonic splicing silencers. Cell 119:831–845. doi: 10.1016/j.cell.2004.11.010 PubMedCrossRefGoogle Scholar
  247. Webb TR et al (2012) Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23). Hum Mol Genet 21:3647–3654. doi: 10.1093/hmg/dds194 PubMedPubMedCentralCrossRefGoogle Scholar
  248. Will CL, Luhrmann R (2011) Spliceosome structure and function. Cold Spring Harbor Perspect Biol. doi: 10.1101/cshperspect.a003707 Google Scholar
  249. Will CL, Schneider C, Reed R, Luhrmann R (1999) Identification of both shared and distinct proteins in the major and minor spliceosomes. Science 284:2003–2005PubMedCrossRefGoogle Scholar
  250. Williams GT, Farzaneh F (2012) Are snoRNAs and snoRNA host genes new players in cancer? Nat Rev Cancer 12:84–88. doi: 10.1038/nrc3195 PubMedGoogle Scholar
  251. Wilusz JE (2015) Repetitive elements regulate circular RNA biogenesis. Mob Genet Elem 5:1–7. doi: 10.1080/2159256X.2015.1045682 CrossRefGoogle Scholar
  252. Witten JT, Ule J (2011) Understanding splicing regulation through RNA splicing maps. Trends Genet 27:89–97. doi: 10.1016/j.tig.2010.12.001 PubMedPubMedCentralCrossRefGoogle Scholar
  253. Wong JJ et al (2013) Orchestrated intron retention regulates normal granulocyte differentiation. Cell 154:583–595. doi: 10.1016/j.cell.2013.06.052 PubMedCrossRefGoogle Scholar
  254. Wu S, Romfo CM, Nilsen TW, Green MR (1999) Functional recognition of the 3′ splice site AG by the splicing factor U2AF35. Nature 402:832–835. doi: 10.1038/45590 PubMedCrossRefGoogle Scholar
  255. Xiong HY et al (2015) RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Science 347:1254806. doi: 10.1126/science.1254806 PubMedCrossRefGoogle Scholar
  256. Yagi M, Takeshima Y, Wada H, Nakamura H, Matsuo M (2003) Two alternative exons can result from activation of the cryptic splice acceptor site deep within intron 2 of the dystrophin gene in a patient with as yet asymptomatic dystrophinopathy. Hum Genet 112:164–170. doi: 10.1007/s00439-002-0854-8 PubMedGoogle Scholar
  257. Yap K, Lim ZQ, Khandelia P, Friedman B, Makeyev EV (2012) Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention. Genes Dev 26:1209–1223. doi: 10.1101/gad.188037.112 PubMedPubMedCentralCrossRefGoogle Scholar
  258. Yasmeen S et al (2014) Occipital horn syndrome and classical Menkes Syndrome caused by deep intronic mutations, leading to the activation of ATP7A pseudo-exon. Eur J Hum Genet 22:517–521. doi: 10.1038/ejhg.2013.191 PubMedCrossRefGoogle Scholar
  259. Yasuda H, Oh CD, Chen D, de Crombrugghe B, Kim JH (2017) A novel regulatory mechanism of type II collagen expression via a SOX9-dependent enhancer in intron 6. J Biol Chem 292:528–538. doi: 10.1074/jbc.M116.758425 PubMedCrossRefGoogle Scholar
  260. Yu Y et al (2008) Dynamic regulation of alternative splicing by silencers that modulate 5′ splice site competition. Cell 135:1224–1236. doi: 10.1016/j.cell.2008.10.046 PubMedPubMedCentralCrossRefGoogle Scholar
  261. Zamore PD, Patton JG, Green MR (1992) Cloning and domain structure of the mammalian splicing factor U2AF. Nature 355:609–614. doi: 10.1038/355609a0 PubMedCrossRefGoogle Scholar
  262. Zhang XH, Chasin LA (2004) Computational definition of sequence motifs governing constitutive exon splicing. Genes Dev 18:1241–1250. doi: 10.1101/gad.1195304 PubMedPubMedCentralCrossRefGoogle Scholar
  263. Zhang Y et al (2013) Circular intronic long noncoding RNAs. Mol Cell 51:792–806. doi: 10.1016/j.molcel.2013.08.017 PubMedCrossRefGoogle Scholar
  264. Zorio DA, Blumenthal T (1999) Both subunits of U2AF recognize the 3′ splice site in Caenorhabditis elegans. Nature 402:835–838. doi: 10.1038/45597 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Rita Vaz-Drago
    • 1
  • Noélia Custódio
    • 1
  • Maria Carmo-Fonseca
    • 1
  1. 1.Instituto de Medicina Molecular, Faculdade de MedicinaUniversidade de LisboaLisbonPortugal

Personalised recommendations