title: Alternative splicing and retinal degeneration.
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.
authors: Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors: M M
authors: MM
authors: Liu
authors: D J
authors: DJ
authors: Zack
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D006801:Humans; D009154:Mutation; D059368:RNA Isoforms; D022821:RNA Splice Sites; D012174:Retinitis Pigmentosa / Q000235:genetics*; D017381:Spliceosomes
chemical_list: D059368:RNA Isoforms; D022821:RNA Splice Sites
keywords: alternative splicing; retinal degeneration; retinitis pigmentosa; small molecules
references: Mol Vis. 2006 Oct 26;12:1259-71
references: 17110909
references: Invest Ophthalmol Vis Sci. 2010 Feb;51(2):1036-43
references: 19710410
references: Hum Mol Genet. 2000 Mar 1;9(4):645-51
references: 10699188
references: Trends Mol Med. 2012 Aug;18(8):472-82
references: 22819011
references: Hum Mol Genet. 2006 Jun 1;15(11):1847-57
references: 16632484
references: Nat Rev Mol Cell Biol. 2009 Nov;10(11):741-54
references: 19773805
references: Am J Hum Genet. 2011 May 13;88(5):643-9
references: 21549338
references: Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9808-13
references: 11504946
references: PLoS One. 2011;6(6):e18643
references: 21694768
references: Exp Cell Res. 2005 Jan 1;302(1):61-8
references: 15541726
references: Nature. 2010 Feb 11;463(7282):818-22
references: 20081832
references: EMBO J. 2002 Mar 1;21(5):1148-57
references: 11867543
references: Am J Ophthalmol. 2002 Feb;133(2):203-10
references: 11812423
references: Hum Mol Genet. 2002 Aug 1;11(16):1879-86
references: 12140190
references: Nat Rev Neurosci. 2007 Nov;8(11):819-31
references: 17895907
references: Sci Transl Med. 2009 Nov 4;1(5):5ra12
references: 20161659
references: Nucleic Acids Res. 2002 Sep 1;30(17):3754-66
references: 12202761
references: Mol Ther. 2011 May;19(5):936-41
references: 21326217
references: Hum Mutat. 2008 Jun;29(6):869-78
references: 18412284
references: Hum Mol Genet. 2002 Jan 1;11(1):87-92
references: 11773002
references: J Cell Biol. 2011 Oct 3;195(1):27-40
references: 21949414
references: Mol Vis. 2004 May 20;10:361-5
references: 15162096
references: Hum Mutat. 2007 Aug;28(8):797-807
references: 17405150
references: Mol Cell. 2001 Aug;8(2):375-81
references: 11545739
references: J Biol Chem. 2005 Sep 30;280(39):33580-7
references: 16043481
references: Lancet. 2008 Jun 21;371(9630):2120-33
references: 18572081
references: Hum Genet. 1992 Sep-Oct;90(1-2):41-54
references: 1427786
references: Hum Mol Genet. 2001 Nov 15;10(24):2841-9
references: 11734549
references: J Neurosci. 2005 Jan 19;25(3):748-57
references: 15659613
references: J Biol Chem. 2010 Feb 19;285(8):5532-40
references: 19906640
references: Eur J Hum Genet. 2002 Apr;10(4):245-9
references: 12032732
references: Drug Discov Today. 2013 Jan;18(1-2):43-9
references: 22885522
references: Mol Cell Biol. 1997 Jul;17(7):3580-8
references: 9199293
references: Annu Rev Biochem. 2003;72:291-336
references: 12626338
references: Nat Genet. 2000 Aug;25(4):462-6
references: 10932196
references: Biochem Biophys Res Commun. 1994 Aug 30;203(1):289-95
references: 8074668
references: Am J Hum Genet. 2009 Nov;85(5):617-27
references: 19878916
references: BMC Med Genet. 2010 Oct 12;11:145
references: 20939871
references: Hum Mutat. 2002 May;19(5):486-500
references: 11968081
references: Hum Mol Genet. 2007 Jul 15;16(14):1699-707
references: 17517693
references: J Biol Chem. 2004 Jun 4;279(23):24246-54
references: 15010457
references: Hum Mol Genet. 2001 Jul 15;10(15):1555-62
references: 11468273
references: Hum Mol Genet. 2011 Jun 1;20(11):2116-30
references: 21378395
references: Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1628-35
references: 19834030
references: Neurobiol Dis. 2007 May;26(2):291-300
references: 17350276
references: PLoS One. 2011 Jan 19;6(1):e15860
references: 21283520
references: Am J Med Genet A. 2003 Sep 1;121A(3):235-9
references: 12923864
references: Invest Ophthalmol Vis Sci. 2011 Jun 01;52(6):3723-9
references: 21357407
references: Nat Rev Drug Discov. 2012 Jan 20;11(2):125-40
references: 22262036
references: Am J Ophthalmol. 2004 Sep;138(3):504-5
references: 15364249
references: Nat Chem Biol. 2007 Sep;3(9):570-5
references: 17643112
references: RNA. 1995 Oct;1(8):763-71
references: 7493322
references: ACS Chem Biol. 2011 Jun 17;6(6):582-9
references: 21344922
references: Science. 2003 Dec 19;302(5653):2141-4
references: 14684825
references: Lancet. 2006 Nov 18;368(9549):1795-809
references: 17113430
references: Surv Ophthalmol. 2003 Mar-Apr;48(2):191-203
references: 12686304
references: Am J Ophthalmol. 2002 Nov;134(5):728-34
references: 12429250
references: Invest Ophthalmol Vis Sci. 2011 Jan 05;52(1):190-8
references: 20811066
references: Hum Mol Genet. 2002 Dec 1;11(25):3209-19
references: 12444105
references: Invest Ophthalmol Vis Sci. 2004 Jan;45(1):36-41
references: 14691151
references: Hum Mutat. 2011 Jul;32(7):815-24
references: 21520335
references: Am J Ophthalmol. 1984 Mar;97(3):357-65
references: 6702974
references: RNA. 2005 May;11(5):533-57
references: 15840809
references: Trends Biochem Sci. 2000 Aug;25(8):381-8
references: 10916158
references: Mol Cell Neurosci. 2001 Jul;18(1):80-90
references: 11461155
references: Am J Hum Genet. 1997 Sep;61(3):571-80
references: 9326322
references: Nat Commun. 2011;2:308
references: 21556062
references: Invest Ophthalmol Vis Sci. 2003 May;44(5):2171-7
references: 12714658
references: Invest Ophthalmol Vis Sci. 2011 Jul 15;52(8):5189-201
references: 21546531
references: Hum Mol Genet. 2001 Aug 1;10(16):1619-26
references: 11487564
references: Trends Biochem Sci. 2000 Mar;25(3):106-10
references: 10694877
references: In Silico Biol. 2004;4(4):387-93
references: 15217358