Home LiteratureArticle Details
PMID: 23647439 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Alternative splicing and retinal degeneration.

Clinical genetics ·Vol. 84 ·No. 2 ·2013-08-00 ·Pages 142-9

Liu MM, Zack DJ

Abstract

Alternative splicing is highly regulated in tissue-specific and development-specific patterns, and it has been estimated that 15% of disease-causing point mutations affect pre-mRNA splicing. In this review, we consider the cis-acting splice site and trans-acting splicing factor mutations that affect pre-mRNA splicing and contribute to retinal degeneration. Numerous splice site mutations have been identified in retinitis pigmentosa (RP) and various cone-rod dystrophies. Mutations in alternatively spliced retina-specific exons of the widely expressed RPGR and COL2A1 genes lead primarily to X-linked RP and ocular variants of Stickler syndrome, respectively. Furthermore, mutations in general pre-mRNA splicing factors, such as PRPF31, PRPF8, and PRPF3, predominantly cause autosomal dominant RP. These findings suggest an important role for pre-mRNA splicing in retinal homeostasis and the pathogenesis of retinal degenerative diseases. The development of novel therapeutic strategies to modulate aberrant splicing, including small molecule-based therapies, has the potential to lead to new treatments for retinal degenerative diseases.

Keywords
alternative splicing retinal degeneration retinitis pigmentosa small molecules
MeSH Terms
Alternative Splicing Animals Humans Mutation RNA Isoforms RNA Splice Sites Retinitis Pigmentosa/genetics Spliceosomes
Chemicals
RNA Isoforms RNA Splice Sites
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Liu M M
Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Zack D J
References (72)
72 references, click to expand
  1. Pre-mRNA splicing and retinitis pigmentosa.
    Mol Vis. 2006 Oct 26;12:1259-71 PMID: 17110909
  2. Mutations in ASCC3L1 on 2q11.2 are associated with autosomal dominant retinitis pigmentosa in a Chinese family.
    Invest Ophthalmol Vis Sci. 2010 Feb;51(2):1036-43 PMID: 19710410
  3. Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat.
    Hum Mol Genet. 2000 Mar 1;9(4):645-51 PMID: 10699188
  4. Pre-mRNA splicing in disease and therapeutics.
    Trends Mol Med. 2012 Aug;18(8):472-82 PMID: 22819011
  5. In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse.
    Hum Mol Genet. 2006 Jun 1;15(11):1847-57 PMID: 16632484
  6. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches.
    Nat Rev Mol Cell Biol. 2009 Nov;10(11):741-54 PMID: 19773805
  7. A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa.
    Am J Hum Genet. 2011 May 13;88(5):643-9 PMID: 21549338
  8. Treatment of spinal muscular atrophy by sodium butyrate.
    Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9808-13 PMID: 11504946
  9. Small molecule amiloride modulates oncogenic RNA alternative splicing to devitalize human cancer cells.
    PLoS One. 2011;6(6):e18643 PMID: 21694768
  10. Association of PAP-1 and Prp3p, the products of causative genes of dominant retinitis pigmentosa, in the tri-snRNP complex.
    Exp Cell Res. 2005 Jan 1;302(1):61-8 PMID: 15541726
  11. Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication.
    Nature. 2010 Feb 11;463(7282):818-22 PMID: 20081832
  12. Protein 61K, encoded by a gene (PRPF31) linked to autosomal dominant retinitis pigmentosa, is required for U4/U6*U5 tri-snRNP formation and pre-mRNA splicing.
    EMBO J. 2002 Mar 1;21(5):1148-57 PMID: 11867543
  13. A frame shift mutation in a tissue-specific alternatively spliced exon of collagen 2A1 in Wagner's vitreoretinal degeneration.
    Am J Ophthalmol. 2002 Feb;133(2):203-10 PMID: 11812423
  14. Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6.
    Hum Mol Genet. 2002 Aug 1;11(16):1879-86 PMID: 12140190
  15. Neuronal regulation of alternative pre-mRNA splicing.
    Nat Rev Neurosci. 2007 Nov;8(11):819-31 PMID: 17895907
  16. Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy.
    Sci Transl Med. 2009 Nov 4;1(5):5ra12 PMID: 20161659
  17. Genome-wide detection of tissue-specific alternative splicing in the human transcriptome.
    Nucleic Acids Res. 2002 Sep 1;30(17):3754-66 PMID: 12202761
  18. Gene therapeutic approach using mutation-adapted U1 snRNA to correct a RPGR splice defect in patient-derived cells.
    Mol Ther. 2011 May;19(5):936-41 PMID: 21326217
  19. Transcriptional expression of cis-acting and trans-acting splicing mutations cause autosomal dominant retinitis pigmentosa.
    Hum Mutat. 2008 Jun;29(6):869-78 PMID: 18412284
  20. Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa.
    Hum Mol Genet. 2002 Jan 1;11(1):87-92 PMID: 11773002
  21. Stress-responsive maturation of Clk1/4 pre-mRNAs promotes phosphorylation of SR splicing factor.
    J Cell Biol. 2011 Oct 3;195(1):27-40 PMID: 21949414
  22. A novel PRPF31 splice-site mutation in a Chinese family with autosomal dominant retinitis pigmentosa.
    Mol Vis. 2004 May 20;10:361-5 PMID: 15162096
  23. Identification and characterization of a novel RPGR isoform in human retina.
    Hum Mutat. 2007 Aug;28(8):797-807 PMID: 17405150
  24. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11).
    Mol Cell. 2001 Aug;8(2):375-81 PMID: 11545739
  25. RPGR-ORF15, which is mutated in retinitis pigmentosa, associates with SMC1, SMC3, and microtubule transport proteins.
    J Biol Chem. 2005 Sep 30;280(39):33580-7 PMID: 16043481
  26. Spinal muscular atrophy.
    Lancet. 2008 Jun 21;371(9630):2120-33 PMID: 18572081
  27. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences.
    Hum Genet. 1992 Sep-Oct;90(1-2):41-54 PMID: 1427786
  28. Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients.
    Hum Mol Genet. 2001 Nov 15;10(24):2841-9 PMID: 11734549
  29. Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells.
    J Neurosci. 2005 Jan 19;25(3):748-57 PMID: 15659613
  30. Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis.
    J Biol Chem. 2010 Feb 19;285(8):5532-40 PMID: 19906640
  31. Mutations in a protein target of the Pim-1 kinase associated with the RP9 form of autosomal dominant retinitis pigmentosa.
    Eur J Hum Genet. 2002 Apr;10(4):245-9 PMID: 12032732
  32. The development and application of small molecule modulators of SF3b as therapeutic agents for cancer.
    Drug Discov Today. 2013 Jan;18(1-2):43-9 PMID: 22885522
  33. Prp31p promotes the association of the U4/U6 x U5 tri-snRNP with prespliceosomes to form spliceosomes in Saccharomyces cerevisiae.
    Mol Cell Biol. 1997 Jul;17(7):3580-8 PMID: 9199293
  34. Mechanisms of alternative pre-messenger RNA splicing.
    Annu Rev Biochem. 2003;72:291-336 PMID: 12626338
  35. Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa.
    Nat Genet. 2000 Aug;25(4):462-6 PMID: 10932196
  36. Identification of alternatively spliced variants of type II procollagen in vitreous.
    Biochem Biophys Res Commun. 1994 Aug 30;203(1):289-95 PMID: 8074668
  37. Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs.
    Am J Hum Genet. 2009 Nov;85(5):617-27 PMID: 19878916
  38. Prevalence and novelty of PRPF31 mutations in French autosomal dominant rod-cone dystrophy patients and a review of published reports.
    BMC Med Genet. 2010 Oct 12;11:145 PMID: 20939871
  39. Mutations of RPGR in X-linked retinitis pigmentosa (RP3).
    Hum Mutat. 2002 May;19(5):486-500 PMID: 11968081
  40. Mutations in splicing factor PRPF3, causing retinal degeneration, form detrimental aggregates in photoreceptor cells.
    Hum Mol Genet. 2007 Jul 15;16(14):1699-707 PMID: 17517693
  41. Manipulation of alternative splicing by a newly developed inhibitor of Clks.
    J Biol Chem. 2004 Jun 4;279(23):24246-54 PMID: 15010457
  42. Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13).
    Hum Mol Genet. 2001 Jul 15;10(15):1555-62 PMID: 11468273
  43. PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa.
    Hum Mol Genet. 2011 Jun 1;20(11):2116-30 PMID: 21378395
  44. Mutation- and tissue-specific alterations of RPGR transcripts.
    Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1628-35 PMID: 19834030
  45. Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa.
    Neurobiol Dis. 2007 May;26(2):291-300 PMID: 17350276
  46. Temporal and tissue specific regulation of RP-associated splicing factor genes PRPF3, PRPF31 and PRPC8--implications in the pathogenesis of RP.
    PLoS One. 2011 Jan 19;6(1):e15860 PMID: 21283520
  47. Novel deletion in the pre-mRNA splicing gene PRPF31 causes autosomal dominant retinitis pigmentosa in a large Chinese family.
    Am J Med Genet A. 2003 Sep 1;121A(3):235-9 PMID: 12923864
  48. Cellular expression and siRNA-mediated interference of rhodopsin cis-acting splicing mutants associated with autosomal dominant retinitis pigmentosa.
    Invest Ophthalmol Vis Sci. 2011 Jun 01;52(6):3723-9 PMID: 21357407
  49. RNA therapeutics: beyond RNA interference and antisense oligonucleotides.
    Nat Rev Drug Discov. 2012 Jan 20;11(2):125-40 PMID: 22262036
  50. A presumed missense mutation of RPGR causes abnormal RNA splicing with exon skipping.
    Am J Ophthalmol. 2004 Sep;138(3):504-5 PMID: 15364249
  51. Splicing factor SF3b as a target of the antitumor natural product pladienolide.
    Nat Chem Biol. 2007 Sep;3(9):570-5 PMID: 17643112
  52. Finding splice sites within a wilderness of RNA.
    RNA. 1995 Oct;1(8):763-71 PMID: 7493322
  53. Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing.
    ACS Chem Biol. 2011 Jun 17;6(6):582-9 PMID: 21344922
  54. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays.
    Science. 2003 Dec 19;302(5653):2141-4 PMID: 14684825
  55. Retinitis pigmentosa.
    Lancet. 2006 Nov 18;368(9549):1795-809 PMID: 17113430
  56. Clinical variability of Stickler syndrome: role of exon 2 of the collagen COL2A1 gene.
    Surv Ophthalmol. 2003 Mar-Apr;48(2):191-203 PMID: 12686304
  57. Radial perivascular retinal degeneration: a key to the clinical diagnosis of an ocular variant of Stickler syndrome with minimal or no systemic manifestations.
    Am J Ophthalmol. 2002 Nov;134(5):728-34 PMID: 12429250
  58. Three gene-targeted mouse models of RNA splicing factor RP show late-onset RPE and retinal degeneration.
    Invest Ophthalmol Vis Sci. 2011 Jan 05;52(1):190-8 PMID: 20811066
  59. Disease mechanism for retinitis pigmentosa (RP11) caused by mutations in the splicing factor gene PRPF31.
    Hum Mol Genet. 2002 Dec 1;11(25):3209-19 PMID: 12444105
  60. Dominant, gain-of-function mutant produced by truncation of RPGR.
    Invest Ophthalmol Vis Sci. 2004 Jan;45(1):36-41 PMID: 14691151
  61. U1 snRNA-mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation.
    Hum Mutat. 2011 Jul;32(7):815-24 PMID: 21520335
  62. Prevalence of retinitis pigmentosa in Maine.
    Am J Ophthalmol. 1984 Mar;97(3):357-65 PMID: 6702974
  63. Prp8 protein: at the heart of the spliceosome.
    RNA. 2005 May;11(5):533-57 PMID: 15840809
  64. Alternative pre-mRNA splicing: the logic of combinatorial control.
    Trends Biochem Sci. 2000 Aug;25(8):381-8 PMID: 10916158
  65. Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors.
    Mol Cell Neurosci. 2001 Jul;18(1):80-90 PMID: 11461155
  66. Analysis of the RPGR gene in 11 pedigrees with the retinitis pigmentosa type 3 genotype: paucity of mutations in the coding region but splice defects in two families.
    Am J Hum Genet. 1997 Sep;61(3):571-80 PMID: 9326322
  67. Chemical treatment enhances skipping of a mutated exon in the dystrophin gene.
    Nat Commun. 2011;2:308 PMID: 21556062
  68. Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa.
    Invest Ophthalmol Vis Sci. 2003 May;44(5):2171-7 PMID: 12714658
  69. Misexpression of the constitutive Rpgr(ex1-19) variant leads to severe photoreceptor degeneration.
    Invest Ophthalmol Vis Sci. 2011 Jul 15;52(8):5189-201 PMID: 21546531
  70. Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice.
    Hum Mol Genet. 2001 Aug 1;10(16):1619-26 PMID: 11487564
  71. Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases.
    Trends Biochem Sci. 2000 Mar;25(3):106-10 PMID: 10694877
  72. Distributions of exons and introns in the human genome.
    In Silico Biol. 2004;4(4):387-93 PMID: 15217358
Article Info
Journal
Clinical genetics
Abbr.
Clin Genet
ISSN
1399-0004
DOI
10.1111/cge.12181
Published
2013-08-00
Epub
2013-00-05
Pages
142-9
Language
English
Region
Denmark
NLM ID
0253664
PMCID
PMC4147722
Subset
IM
Grants
NIGMS NIH HHS · T32 GM007309 · United States
NEI NIH HHS · R01 EY009769 · United States
NEI NIH HHS · P30 EY001765 · United States
NEI NIH HHS · P30EY001765 · United States
NIGMS NIH HHS · T32GM007309 · United States
NEI NIH HHS · R01EY009769 · United States
External Links
PubMed source DOI: 10.1111/cge.12181 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2