Splice-shifting oligonucleotide (SSO) mediated blocking of an exonic splicing enhancer (ESE) created by the prevalent c.903+469T>C MTRR mutation corrects splicing and restores enzyme activity in patient cells

Nucleic Acids Research

Volumn 43, Issue 9, 2015, Pages 4627-4639

  Palhais, Bruno ^a   Præstegaard, Veronica S ^a   Sabaratnam, Rugivan ^a   Doktor, Thomas Koed ^a   Lutz, Seraina ^b   Burda, Patricie ^b   Suormala, Terttu ^b   Baumgartner, Matthias ^b   Fowler, Brian ^b   Bruun, Gitte Hoffmann ^a   Andersen, Henriette Skovgaard ^a   Kozich, Viktor ^c   Andresen, Brage Storstein ^a  

^a UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^b UNIVERSITY CHILDREN S HOSPITAL   (Switzerland)

^c Charles University in Prague and General University Hospital in Prague   (Czech Republic)

Author keywords

[No Author keywords available]

Indexed keywords

HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN; METHIONINE SYNTHASE REDUCTASE; OLIGONUCLEOTIDE; PROTEIN HNRNP A1; SPLICE SHIFTING OLIGONUCLEOTIDE; UNCLASSIFIED DRUG; FERREDOXIN NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE REDUCTASE; REGULATORY RNA SEQUENCE; RNA SPLICING;

ARTICLE; CONTROLLED STUDY; ENHANCER REGION; ENZYME ACTIVITY; EXON; EXONIC SPLICING ENHANCER; GENE MUTATION; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; MTRR GENE; POINT MUTATION; PRIORITY JOURNAL; PSEUDOEXON; RNA SPLICING; CELL CULTURE; CELL LINE; ENZYMOLOGY; GENETICS; HEK293 CELL LINE; HOMOCYSTINURIA; MEGALOBLASTIC ANEMIA; METABOLISM; MUTATION; REGULATORY RNA SEQUENCE;

ANEMIA, MEGALOBLASTIC; CELL LINE; CELLS, CULTURED; EXONS; FERREDOXIN-NADP REDUCTASE; HEK293 CELLS; HOMOCYSTINURIA; HUMANS; MUTATION; OLIGONUCLEOTIDES; REGULATORY SEQUENCES, RIBONUCLEIC ACID; RNA SPLICE SITES; RNA SPLICING;

EID: 84936818673     PISSN: 03051048     EISSN: 13624962     Source Type: Journal    
DOI: 10.1093/nar/gkv275     Document Type: Article

References (54)

1. Shapiro, M.B. and Senapathy, P. (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res., 15, 7155-7174.
2. Roca, X., Olson, A.J., Rao, A.R., Enerly, E., Kristensen, V.N., Borresen-Dale, A.L., Andresen, B.S., Krainer, A.R. and Sachidanandam, R. (2008) Features of 5-splice-site efficiency derived from disease-causing mutations and comparative genomics. Genome Res., 18, 77-87.
3. Buratti, E., Baralle, M. and Baralle, F.E. (2006) Defective splicing, disease and therapy: searching for master checkpoints in exon definition. Nucleic Acids Res., 34, 3494-510.
4. Cartegni, L., Chew, S.L. and Krainer, A.R. (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat. Rev. Genet., 3, 285-298.
5. Dreyfuss, G., Kim, V.N. and Kataoka, N. (2002). Messenger-RNA-binding proteins and the messages they carry. Nat. Rev. Mol. Cell. Biol., 3, 195-205.
6. Lim, K.H., Ferraris, L., Filloux, M.E., Raphael, B.J. and Fairbrother, W.G. (2011) Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. Proc. Natl. Acad. Sci. U. S. A., 108, 11093-11098.
7. Sterne-Weiler, T., Howard, J., Mort, M., Cooper, D.N. and Sanford, J.R. (2011) Loss of exon identity is a common mechanism of human inherited disease. Genome Res., 21, 1563-1571.
8. Matern, D., He, M., Berry, S.A., Rinaldo, P., Whitley, C.B., Madsen, P.P., van Calcar, S.C., Lussky, R.C., Andresen, B.S., Wolff, J.A. et al. (2003) Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in the Hmong population by newborn screening using tandem mass spectrometry. Pediatrics., 112, 74-78.
9. Wang, G.S. and Cooper, T.A. (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat. Rev. Genet., 8, 749-761.
10. Andresen, B.S. and Krainer, A.R. (2009) When the genetic code is not enough-How sequence variation can affect pre-mRNA splicing and cause (complex) disease. In: Almasy, L and Al-Chalabi, A (eds). Genetics of Complex Human Diseases. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. pp. 165-182.
11. Dobrowolski, S.F., Andersen, H.S., Doktor, T.K. and Andresen, B.S. (2010) The PAH c.30C>G synonymous variation (p.G10G) creates a common exonic splicing silencer. Mol. Genet. Metab., 100, 316-323.
12. Heintz, C., Dobrowolski, S.F., Andersen, H.S., Demirkol, M., Blau, N. and Andresen, B.S. (2012) Splicing of phenylalanine hydroxylase (PAH) exon 11 is vulnerable-Molecular pathology of mutations in PAH exon 11. Mol. Genet. Metab., 106, 403-411.
13. Olsen, R.K.J., Brer, S., Sabaratnam, R., Doktor, T.K., Andersen, H.S., Bruun, G.H., Gahrn, B., Stenbroen, V., Olpin, S.E., Dobbie, A. et al. (2014) The ETFDH c.158A>G variant disrupts the balanced interplay of ESE-and ESS-binding proteins thereby causing missplicing and multiple acyl-CoA dehydrogenation deficiency. Hum. Mutat., 35, 86-95.
14. Sun, H. and Chasin, L.A. (2000) Multiple splicing defects in an intronic false exon. Mol. Cell. Biol., 20, 6414-6425.
15. Sironi, M., Menozzi, G., Riva, L., Cagliani, R., Comi, G.P., Bresolin, N., Giorda, R. and Pozzoli, U. (2004) Silencer elements as possible inhibitors of pseudoexon splicing. Nucleic Acids Res, 32, 1783-1791.
16. Zhang, X.H. and Chasin, L.A. (2004) Computational definition of sequence motifs governing constitutive exon splicing. Genes Dev., 18, 1241-1250.
17. Dhir, A. and Buratti, E. (2010) Alternative splicing: role of pseudoexons in human disease and potential therapeutic strategies. FEBS. J., 277, 841-855.
18. Homolova, K., Zavadakova, P., Doktor, T.K., Schroeder, L.D., Kozich, V. and Andresen, B.S. (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.
19. Ishii, S., Nakao, S., Minamikawa-Tachino, R., Desnick, R.J. and Fan, J.Q. (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.
20. King, K., Flinter, F.A., Nihalani, V. and Green, P.M. (2002) Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome. Hum. Genet., 111, 548-554.
21. Pagani, F., Buratti, E., Stuani, C., Bendix, R., Dork, T. and Baralle, F.E. (2002) A new type of mutation causes a splicing defect in ATM. Nat. Genet., 30, 426-429.
22. Rincon, A., Aguado, C., Desviat, L.R., Sanchez-Alcudia, R., Ugarte, M. and Perez, B. (2007) Propionic and methylmalonic acidemia: antisense therapeutics for intronic variations causing aberrantly spliced messenger RNA. Am. J. Hum. Genet., 81, 1262-1270.
23. Faà, V., Incani, F., Meloni, A., Corda, D., Masala, M., Baffico, A.M., Seia, M., Cao, A. and Rosatelli, M.C. (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.
24. Davis, R.L., Homer, V.M., George, P.M. and Brennan, S.O. (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.
25. Yamaguchi, H., Fujimoto, T., Nakamura, S., Ohmura, K., Mimori, T., Matsuda, F. and Nagata, S. (2010) Aberrant splicing of the milk fat globule-EGF factor 8 (MFG-E8) gene in human systemic lupus erythematosus. Eur. J. Immunol., 40, 1778-2085.
26. Maquat, L.E. (2004) Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol. Cell. Biol., 5, 89-99.
27. Wilson, A., Leclerc, D., Rosenblatt, D.S. and Gravel, R.A. (1999) Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism. Hum. Mol. Genet., 8, 2009-2016.
28. Zavadakova, P., Fowler, B., Suormala, T., Novotna, Z., Mueller, P., Hennermann, J.B., Zeman, J., Vilaseca, M.A., Vilarinho, L., Gutsche, S. et al. (2005) cblE Type of homocystinuria due to methionine synthase reductase deficiency: Functional correction by minigene expression. Hum. Mutat., 25, 239-247.
29. Huemer, M., Burer, C., Jesina, P., Kozich, V., Landolt, M.A., Suormala, T., Fowler, B., Augoustides-Savvopoulou, P., Blair, E., Brennerova et al. (2014) Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data. J. Inherit. Metab. Dis., doi:10.1007/s10545-014-9803-7.
30. Perez, B., Rodriguez-Pascau, L., Vilageliu, L., Grinberg, D., Ugarte, M. and Desviat, L.R. (2010) Present and future of antisense therapy for splicing modulation in inherited metabolic disease. J. Inherit. Metab. Dis., 33, 397-403.
31. Havens, M.A., Duelli, D.M. and Hastings, M.L. (2013) Targeting RNA splicing for disease therapy. Wiley Interdiscip. Rev. RNA, 4, 247-266.
32. Singh, G. and Cooper, T.A. (2006) Minigene reporter for identification and analysis of cis elements and trans factors affecting pre-mRNA splicing. Biotechniques, 41, 177-181.
33. Nielsen, K.B., Sorensen, S., Cartegni, L., Corydon, T.J., Doktor, T.K., Schroeder, L.D., Reinert, L.S., Elpeleg, O., Krainer, A.R., Gregersen, N. et al. (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. Am. J. Hum. Genet., 80, 416-432.
34. Fowler, B. and Jakobs, C. (1998) Post-and prenatal diagnostic methods for the homocystinurias. Eur. J. Pediatr., 157(Suppl 2), S88-S93.
35. Coelho, D., Kim, J.C., Miousse, I.R., Fung, S., du Moulin, M., Buers, I., Suormala, T., Burda, P., Frapolli, M., Stucki, M. et al. (2012) Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat. Genet., 44, 1152-1155.
36. Cartegni, L., Wang, J., Zhu, Z., Zhang, M.Q. and Krainer, A.R. (2003) ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res., 31, 3568-3571.
37. Quinlan, A.R. and Hall, I.M. (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics, 26, 841-842.
38. Cartegni, L., Hastings, M.L., Calarco, J.A., de Stanchina, E. and Krainer, A.R. (2006) Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. Am. J. Hum. Genet., 78, 63-77.
39. Ghigna, C., De Toledo, M., Bonomi, S., Valacca, C., Gallo, S., Apicella, M., Eperon, I., Tazi, J. and Biamonti, G. (2010) Pro-metastatic splicing of Ron proto-oncogene mRNA can be reversed: therapeutic potential of bifunctional oligonucleotides and indole derivatives. RNA Biol., 7, 495-503.
40. Ghigna, C., Giordano, S., Shen, H., Benvenuto, F., Castiglioni, F., Comoglio, P.M., Green, M.R., Riva, S. and Biamonti, G. (2005) Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol. Cell, 20, 881-890.
41. Goncalves, V., Theisen, P., Antunes, O., Medeira, A., Ramos, J.S., Jordan, P. and Isidro, G. (2009) A missense mutation in the APC tumor suppressor gene disrupts an ASF/SF2 splicing enhancer motif and causes pathogenic skipping of exon 14. Mutat. Res., 662, 33-36.
42. Okunola, H.L. and Krainer, A, R. (2009) Cooperative-binding and splicing-repressive properties of hnRNP A1. Mol. Cell. Biol., 29, 5620-5631.
43. Mayeda, A., Helfman, D.M. and Krainer, A.R. (1993) Modulation of exon skipping and inclusion by heterogeneous nuclear ribonucleoprotein A1 and pre-mRNA splicing factor SF2/ASF. Mol. Cell. Biol., 13, 2993-3001.
44. Pollard, A.J., Krainer, A.R., Robson, S.C. and Europe-Finner, G.N. (2002) Alternative splicing of the adenylyl cyclase stimulatory G-protein G alpha(s) is regulated by SF2/ASF and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and involves the use of an unusual TG 3-splice Site. J. Biol. Chem., 277, 15241-15251.
45. Bonomi, S., di Matteo, A., Buratti, E., Cabianca, D.S., Baralle, F.E., Ghigna, C. and Biamonti, G. (2013) HnRNP A1 controls a splicing regulatory circuit promoting mesenchymal-to-epithelial transition. Nucleic Acids Res., 41, 8665-8679.
46. Lappalainen, T., Sammeth, M., Friedlander, M.R., 't Hoen, P.A., Monlong, J., Rivas, M.A., Gonzàlez-Porta, M., Kurbatova, N., Griebel, T., Ferreira, P.G. et al. (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature, 501, 506-511.
47. Katz, Y., Wang, E.T., Airoldi, E.M. and Burge, C.B. (2010) Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat. Methods., 7, 1009-1015.
48. Stucki, M., Suormala, T., Fowler, B., Valle, D. and Baumgartner, M.R. (2009) Cryptic exon activation by disruption of exon splice enhancer: novel mechanism causing 3-methylcrotonyl-CoA carboxylase deficiency. J. Biol. Chem., 284, 28953-28957.
49. van Deutekom, J.C., Bremmer-Bout, M., Janson, A.A., Ginjaar, I.B., Baas, F., den Dunnen, J.T. and van Ommen, G.J. (2001) Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells. Hum.Mol. Genet., 10, 1547-1554.
50. Perez, B., Rincon, A., Jorge-Finnigan, A., Richard, E., Merinero, B., Ugarte, M. and Desviat, L.R. (2009) Pseudoexon exclusion by antisense therapy in methylmalonic aciduria (MMAuria). Hum. Mutat., 30, 1676-1682.
51. Rodrguez-Pascau, L., Coll, M.J., Vilageliu, L. and 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.
52. Vega, A.I., Perez-Cerda, C., Desviat, L.R., Matthijs, G., Ugarte, M. and 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.
53. Hua, Y., Sahashi, K., Hung, G., Rigo, F., Passini, M.A., Bennett, C.F. and Krainer, A.R. (2010) Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev., 24, 1634-1644.
54. Blazquez, L., Aiastui, A., Goicoechea, M., Martins de Araujo, M., Avril, A., Beley, C., Garca, L., Valcarcel, J., Fortes, P. and Lopez de Munain, A. (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.