前体mRNA剪接因子基因突变与视网膜色素变性的研究进展

doi:10.3969/j.issn.1674-490X.2023.01.002

摘要/Abstract

摘要： 视网膜色素变性(retinitis pigmentosa, RP)是一种遗传性进行性视细胞损伤性疾病,具有基因型和表型异质性。目前已鉴定的RP致病基因达到103个,其中有一类基因(PRPF3、PRPF4、PRPF6、PRPF8、PRPF31、SNRNP200、RP9和DHX38)与前体mRNA剪接相关,该类基因全身广泛表达,但其突变后引起RP这种组织特异性表型疾病的机制目前尚不清楚。现汇总近年来国内外研究进展,介绍前体mRNA的剪接过程、前体mRNA剪接因子在剪接过程中的作用及前体mRNA剪接因子导致RP的疾病模型,并探讨前体mRNA剪接因子突变导致RP的致病机制。

关键词: 视网膜色素变性, 前体mRNA剪接因子, 疾病模型, 致病机制

Abstract: Retinitis pigmentosa(RP)is an inherited disease of progressive damage to visual cells with genotypic and phenotypic heterogeneity. Up to now, 103 RP pathogenic genes have been identified, among which there is a type of genes(PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, RP9, and DHX38)that is related to pre-mRNA splicing. This type of genes is widely expressed throughout the body, but its mutation, the mechanism behind the disease that causes this tissue-specific phenotype of RP is currently unclear. This paper summarized the research progress in recent years,introduced the splicing process of pre-mRNA, the role of pre-mRNA splicing factors in the splicing process, and the disease model of RP caused by pre-mRNA splicing factors, and discussed the mutations of pre-mRNA splicing factors contribute to the pathogenic mechanism of RP.

Key words: retinitis pigmentosa, pre-mRNA processing factors, disease models, pathogenic mechanism

中图分类号:

R774.1

汪晓晨,邴子钰,孔珺. 前体mRNA剪接因子基因突变与视网膜色素变性的研究进展[J]. 医学研究与教育, 2023, 40(1): 10-21.

参考文献

[1] YU H G, PARK U C, YOON C K. Retinitis pigmentosa in Korean patients[M] //Essentials in Ophthalmology. Tokyo: Springer Japan, 2017: 93-104. DOI: 10.1007/978-4-431-56511-6_9.
[2] BERGER W, KLOECKENER-GRUISSEM B, NEIDHARDT J. The molecular basis of human retinal and vitreoretinal diseases[J]. Prog Retin Eye Res, 2010, 29(5): 335-375. DOI: 10.1016/j.preteyeres.2010.03.004.
[3] DAIGER S P. RetNet: Summaries of Genes and Loci Causing Retinal Diseases[EB/OL].(2023-01-10)[2023-02-20]. http://web.sph.uth.edu/RetNet/sum-dis.htm#B-diseases.
[4] LIU M M, ZACK D J. Alternative splicing and retinal degeneration[J]. Clin Genet, 2013, 84(2): 142-149.DOI: 10.1111/cge.12181.
[5] WAHL M C, WILL C L, LÜHRMANN R. The spliceosome: design principles of a dynamic RNP machine[J]. Cell, 2009, 136(4): 701-718. DOI: 10.1016/j.cell.2009.02.009.
[6] MATERA A G, WANG Z F. A day in the life of the spliceosome[J]. Nat Rev Mol Cell Biol, 2014, 15(2): 108-121. DOI: 10.1038/nrm3742.
[7] RAGHUNATHAN P L, GUTHRIE C. RNA unwinding in U4/U6 snRNPs requires ATP hydrolysis and the DEIH-box splicing factor Brr2[J]. Curr Biol, 1998, 8(15): 847-855. DOI: 10.1016/S0960-9822(07)00345-4.
[8] CHAKAROVA C F, HIMS M M, BOLZ H, et al. Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa[J]. Hum Mol Genet, 2002, 11(1): 87-92. DOI: 10.1093/hmg/11.1.87.
[9] NOTTROTT S, URLAUB H, LÜHRMANN R. Hierarchical, clustered protein interactions with U4/U6 snRNA: a biochemical role for U4/U6 proteins[J]. EMBO J, 2002, 21(20): 5527-5538. DOI: 10.1093/emboj/cdf544.
[10] LIU S B, MOZAFFARI-JOVIN S, WOLLENHAUPT J, et al. A composite double-/single-stranded RNA-binding region in protein Prp3 supports tri-snRNP stability and splicing[J]. eLife, 2015, 4: e07320. DOI: 10.7554/eLife.07320.
[11] LIU S B, RAUHUT R, VORNLOCHER H P, et al. The network of protein-protein interactions within the human U4/U6.U5 tri-snRNP[J]. RNA, 2006, 12(7): 1418-1430. DOI: 10.1261/rna.55406.
[12] GAMUNDI M J, HERNAN I, MUNTANYOLA M, et al. Transcriptional expression of cis-acting and trans-acting splicing mutations cause autosomal dominant retinitis pigmentosa[J]. Hum Mutat, 2008, 29(6): 869-878. DOI: 10.1002/humu.20747.
[13] ZHONG Z L, YAN M, SUN W, et al. Two novel mutations in PRPF3 causing autosomal dominant retinitis pigmentosa[J]. Sci Rep, 2016, 6: 37840. DOI: 10.1038/srep37840.
[14] WADA Y, ITABASHI T, SATO H, et al. Clinical features of a Japanese family with autosomal dominant retinitis pigmentosa associated with a Thr494Met mutation in the HPRP3 gene[J]. Graefe's Arch Clin Exp Ophthalmol, 2004, 242(11): 956-961. DOI: 10.1007/s00417-004-0923-x.
[15] INGLEHEARN C F, TARTTELIN E E, KEEN T J, et al. A new dominant retinitis pigmentosa family mapping to the RP18 locus on chromosome 1q11-21[J]. J Med Genet, 1998, 35(9): 788-789. DOI: 10.1136/jmg.35.9.788.
[16] XU S Y, SCHWARTZ M, ROSENBERG T, et al. A ninth locus(RP18)for autosomal dominant retinitis pigmentosa maps in the pericentromeric region of chromosome 1[J]. Hum Mol Genet, 1996, 5(8): 1193-1197. DOI: 10.1093/hmg/5.8.1193.
[17] LINDER B, HIRMER A, GAL A, et al. Identification of a PRPF4 loss-of-function variant that abrogates U4/U6.U5 tri-snRNP integration and is associated with retinitis pigmentosa[J]. PLoS One, 2014, 9(11): e111754. DOI: 10.1371/journal.pone.0111754.
[18] HUANG L L, ZHANG Q, HUANG X, et al. Mutation screening in genes known to be responsible for Retinitis Pigmentosa in 98 Small Han Chinese Families[J]. Sci Rep, 2017, 7(1): 1948. DOI: 10.1038/s41598-017-00963-6.
[19] CHEN X, LIU Y, SHENG X L, et al. PRPF4 mutations cause autosomal dominant retinitis pigmentosa[J]. Hum Mol Genet, 2014, 23(11): 2926-2939. DOI: 10.1093/hmg/ddu005.
[20] BENAGLIO P, SAN JOSE P F, AVILA-FERNANDEZ A, et al. Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa[J]. Mol Vis, 2014, 20: 843-851.
[21] RŬŽIC ˇKOVĂ Š, STANĚK D. Mutations in spliceosomal proteins and retina degeneration[J]. RNA Biol, 2017, 14(5): 544-552. DOI: 10.1080/15476286.2016.1191735.
[22] TANACKOVIC G, RANSIJN A, AYUSO C, et al. A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa[J]. Am J Hum Genet, 2011, 88(5): 643-649. DOI: 10.1016/j.ajhg.2011.04.008.
[23] STANĚK D. Cajal bodies and snRNPs-friends with benefits[J]. RNA Biol, 2017, 14(6): 671-679. DOI: 10.1080/15476286.2016.1231359.
[24] OISHI M, OISHI A, GOTOH N, et al. Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing[J]. Invest Ophthalmol Vis Sci, 2014, 55(11): 7369-7375. DOI: 10.1167/iovs.14-15458.
[25] STANKOVIC ' D, CLAUDIUS A K, SCHERTEL T, et al. A Drosophila model to study retinitis pigmentosa pathology associated with mutations in the core splicing factor Prp8[J]. Dis Model Mech, 2020, 13(6): dmm043174. DOI: 10.1242/dmm.043174.
[26] BOON K L, NORMAN C M, GRAINGER R J, et al. Prp8p dissection reveals domain structure and protein interaction sites[J]. RNA, 2006, 12(2): 198-205. DOI: 10.1261/rna.2281306.
[27] GRAINGER R J, BEGGS J D. Prp8 protein: at the heart of the spliceosome[J]. RNA, 2005, 11(5): 533-557. DOI: 10.1261/rna.2220705.
[28] ESCHER P, PASSARIN O, MUNIER F L, et al. Variability in clinical phenotypes of PRPF8-linked autosomal dominant retinitis pigmentosa correlates with differential PRPF8/SNRNP200 interactions[J]. Ophthalmic Genet, 2018, 39(1): 80-86. DOI: 10.1080/13816810.2017.1393825.
[29] VAN CAUWENBERGH C, COPPIETERS F, ROELS D, et al. Mutations in splicing factor genes are a major cause of autosomal dominant retinitis pigmentosa in Belgian families[J]. PLoS One, 2017, 12(1): e0170038. DOI: 10.1371/journal.pone.0170038.
[30] MOZAFFARI-JOVIN S, WANDERSLEBEN T, SANTOS K F, et al. Novel regulatory principles of the spliceosomal Brr2 RNA helicase and links to retinal disease in humans[J]. RNA Biol, 2014, 11(4): 298-312. DOI: 10.4161/rna.28353.
[31] VAN LITH-VERHOEVEN J J C, VAN DER VELDE-VISSER S D, SOHOCKI M M, et al. Clinical characterization, linkage analysis, and PRPC8 mutation analysis of a family with autosomal dominant retinitis pigmentosa type 13(RP13)[J]. Ophthalmic Genet, 2002, 23(1): 1-12. DOI: 10.1076/opge.23.1.1.2206.
[32] WALIA S, FISHMAN G A, ZERNANT-RAJANG J, et al. Phenotypic expression of a PRPF8 gene mutation in a Large African American family[J]. Arch Ophthalmol, 2008, 126(8): 1127-1132. DOI: 10.1001/archopht.126.8.1127.
[33] TOWNS K V, KIPIOTI A, LONG V, et al. Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes[J]. Hum Mutat, 2010, 31(5): E1361-E1376. DOI: 10.1002/humu.21236.
[34] DEERY E C, VITHANA E N, NEWBOLD R J, et al. Disease mechanism for retinitis pigmentosa(RP11)caused by mutations in the splicing factor gene PRPF31[J]. Hum Mol Genet, 2002, 11(25): 3209-3219. DOI: 10.1093/hmg/11.25.3209.
[35] EVANS K, AL-MAGHTHEH M, FITZKE F W, et al. Bimodal expressivity in dominant retinitis pigmentosa genetically linked to chromosome 19q[J]. Br J Ophthalmol, 1995, 79(9): 841-846. DOI: 10.1136/bjo.79.9.841.
[36] MOORE A T, FITZKE F, JAY M, et al. Autosomal dominant retinitis pigmentosa with apparent incomplete penetrance: a clinical, electrophysiological, psychophysical, and molecular genetic study[J]. Br J Ophthalmol, 1993, 77(8): 473-479. DOI: 10.1136/bjo.77.8.473.
[37] AL-MAGHTHEH M, VITHANA E, TARTTELIN E, et al. Evidence for a major retinitis pigmentosa locus on 19q13.4(RP11)and association with a unique bimodal expressivity phenotype[J]. Am J Hum Genet, 1996, 59(4): 864-871.
[38] RIO FRIO T, WADE N M, RANSIJN A, et al. Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay[J]. J Clin Invest, 2008, 118(4): 1519-1531. DOI: 10.1172/JCI34211.
[39] RIVOLTA C, MCGEE T L, RIO FRIO T, et al. Variation in retinitis pigmentosa-11(PRPF31 or RP11)gene expression between symptomatic and asymptomatic patients with dominant RP11 mutations[J]. Hum Mutat, 2006, 27(7): 644-653. DOI: 10.1002/humu.20325.
[40] ZHAO C, BELLUR D L, LU S S, et al. Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs[J]. Am J Hum Genet, 2009, 85(5): 617-627. DOI: 10.1016/j.ajhg.2009.09.020.
[41] LIU T C, JIN X, ZHANG X M, et al. A novel missense SNRNP200 mutation associated with autosomal dominant retinitis pigmentosa in a Chinese family[J]. PLoS One, 2012, 7(9): e45464. DOI: 10.1371/journal.pone.0045464.
[42] LI N D, MEI H, MACDONALD I M, et al. Mutations in ASCC3L1 on 2q11.2 are associated with autosomal dominant retinitis pigmentosa in a Chinese family[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1036-1043. DOI: 10.1167/iovs.09-3725.
[43] CORDIN O, BEGGS J D. RNA helicases in splicing[J]. RNA Biol, 2013, 10(1): 83-95. DOI: 10.4161/rna.22547.
[44] ZHANG L D, LI X N, HILL R C, et al. Brr2 plays a role in spliceosomal activation in addition to U4/U6 unwinding[J]. Nucleic Acids Res, 2015, 43(6): 3286-3297. DOI: 10.1093/nar/gkv062.
[45] MOZAFFARI-JOVIN S, WANDERSLEBEN T, SANTOS K F, et al. Inhibition of RNA helicase Brr2 by the C-terminal tail of the spliceosomal protein Prp8[J]. Science, 2013, 341(6141): 80-84. DOI: 10.1126/science.1237515.
[46] SMALL E C, LEGGETT S R, WINANS A A, et al. The EF-G-like GTPase Snu114p regulates spliceosome dynamics mediated by Brr2p, a DExD/H box ATPase[J]. Mol Cell, 2006, 23(3): 389-399. DOI: 10.1016/j.molcel.2006.05.043.
[47] ZIVIELLO C, SIMONELLI F, TESTA F, et al. Molecular genetics of autosomal dominant retinitis pigmentosa(ADRP): a comprehensive study of 43 Italian families[J]. J Med Genet, 2005, 42(7): e47. DOI: 10.1136/jmg.2005.031682.
[48] BENAGLIO P, MCGEE T L, CAPELLI L P, et al. Next generation sequencing of pooled samples reveals new SNRNP200 mutations associated with retinitis pigmentosa[J]. Hum Mutat, 2011, 32(6): E2246-E2258. DOI: 10.1002/humu.21485.
[49] MAITA H, HARADA Y, NAGAKUBO D, et al. PAP-1, a novel target protein of phosphorylation by pim-1 kinase[J]. Eur J Biochem, 2000, 267(16): 5168-5178. DOI: 10.1046/j.1432-1327.2000.01585.x.
[50] MAITA H, KITAURA H, ARIGA H, et al. Association of PAP-1 and Prp3p, the products of causative genes of dominant retinitis pigmentosa, in the tri-snRNP complex[J]. Exp Cell Res, 2005, 302(1): 61-68. DOI: 10.1016/j.yexcr.2004.08.022.
[51] WAHL M C, LÜHRMANN R. SnapShot: spliceosome dynamics I[J]. Cell, 2015, 161(6): 1474-1474.e1. DOI: 10.1016/j.cell.2015.05.050.
[52] KEEN T J, HIMS M M, MCKIE A B, et al. Mutations in a protein target of the Pim-1 kinase associated with the RP9 form of autosomal dominant retinitis pigmentosa[J]. Eur J Hum Genet, 2002, 10(4): 245-249. DOI: 10.1038/sj.ejhg.5200797.
[53] JAY M, BIRD A C, MOORE A N, et al. Nine generations of a family with autosomal dominant retinitis pigmentosa and evidence of variable expressivity from census records[J]. J Med Genet, 1992, 29(12): 906-910. DOI: 10.1136/jmg.29.12.906.
[54] KEEN T J, INGLEHEARN C F, GREEN E D, et al. A YAC contig spanning the dominant retinitis pigmentosa locus(RP9)on chromosome 7p[J]. Genomics, 1995, 28(3): 383-388. DOI: 10.1006/geno.1995.1165.
[55] MAITA H, KITAURA H, KEEN T J, et al. PAP-1, the mutated gene underlying the RP9 form of dominant retinitis pigmentosa, is a splicing factor[J]. Exp Cell Res, 2004, 300(2): 283-296. DOI: 10.1016/j.yexcr.2004.07.029.
[56] SULLIVAN L S, BOWNE S J, BIRCH D G, et al. Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families[J]. Invest Ophthalmol Vis Sci, 2006, 47(7): 3052-3064. DOI: 10.1167/iovs.05-1443.
[57] BISCHOF J M, CHIANG A P, SCHEETZ T E, et al. Genome-wide identification of pseudogenes capable of disease-causing gene conversion[J]. Hum Mutat, 2006, 27(6): 545-552. DOI: 10.1002/humu.20335.
[58] LV J N, ZHOU G H, CHEN X J, et al. Targeted RP9 ablation and mutagenesis in mouse photoreceptor cells by CRISPR-Cas9[J]. Sci Rep, 2017, 7: 43062. DOI: 10.1038/srep43062.
[59] HEGELE A, KAMBUROV A, GROSSMANN A, et al. Dynamic protein-protein interaction wiring of the human spliceosome[J]. Mol Cell, 2012, 45(4): 567-580. DOI: 10.1016/j.molcel.2011.12.034.
[60] CORDIN O, HAHN D, BEGGS J D. Structure, function and regulation of spliceosomal RNA helicases[J]. Curr Opin Cell Biol, 2012, 24(3): 431-438. DOI: 10.1016/j.ceb.2012.03.004.
[61] CORDIN O, HAHN D, ALEXANDER R, et al. Brr2p carboxy-terminal Sec63 domain modulates Prp16 splicing RNA helicase[J]. Nucleic Acids Res, 2014, 42(22): 13897-13910. DOI: 10.1093/nar/gku1238.
[62] HOGG R, DE ALMEIDA R A, RUCKSHANTHI J P D, et al. Remodeling of U2-U6 snRNA helix I during pre-mRNA splicing by Prp16 and the NineTeen Complex protein Cwc2[J]. Nucleic Acids Res, 2014, 42(12): 8008-8023. DOI: 10.1093/nar/gku431.
[63] AJMAL M, KHAN M I, NEVELING K, et al. A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma[J]. J Med Genet, 2014, 51(7): 444-448. DOI: 10.1136/jmedgenet-2014-102316.
[64] LATIF Z, CHAKCHOUK I, SCHRAUWEN I, et al. Confirmation of the role of DHX38 in the etiology of early-onset retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 2018, 59(11): 4552-4557. DOI: 10.1167/iovs.18-23849.
[65] BERGET S M, MOORE C, SHARP P A. Spliced segments at the 5' terminus of adenovirus 2 late mRNA[J]. Proc Natl Acad Sci USA, 1977, 74(8): 3171-3175. DOI: 10.1073/pnas.74.8.3171.
[66] HOSSAIN M A, JOHNSON T L. Using yeast genetics to study splicing mechanisms[M] //Methods in Molecular Biology. Totowa, NJ: Humana Press, 2014: 285-298. DOI: 10.1007/978-1-62703-980-2_21.
[67] ANTHONY J G, WEIDENHAMMER E M, WOOLFORD J L Jr. The yeast Prp3 protein is a U4/U6 snRNP protein necessary for integrity of the U4/U6 snRNP and the U4/U6.U5 tri-snRNP[J]. RNA, 1997, 3(10): 1143-1152.
[68] ABOVICH N, LEGRAIN P, ROSBASH M. The yeast PRP6 gene encodes a U4/U6 small nuclear ribonucleoprotein particle(snRNP)protein, and the PRP9 gene encodes a protein required for U2 snRNP binding[J]. Mol Cell Biol, 1990, 10(12): 6417-6425. DOI: 10.1128/mcb.10.12.6417-6425.1990.
[69] MADDOCK J R, ROY J, WOOLFORD J L Jr. Six novel genes necessary for pre-mRNA splicing in Saccharomyces cerevisiae[J]. Nucleic Acids Res, 1996, 24(6): 1037-1044. DOI: 10.1093/nar/24.6.1037.
[70] PENA V, LIU S B, BUJNICKI J M, et al. Structure of a multipartite protein-protein interaction domain in splicing factor Prp8 and its link to Retinitis pigmentosa[J]. Mol Cell, 2007, 25(4): 615-624. DOI: 10.1016/j.molcel.2007.01.023.
[71] ZHENG S S, HAN R Y, XIANG L, et al. Versatile genome engineering techniques advance human ocular disease researches in zebrafish[J]. Front Cell Dev Biol, 2018, 6: 75. DOI: 10.3389/fcell.2018.00075.
[72] AMSTERDAM A, NISSEN R M, SUN Z X, et al. Identification of 315 genes essential for early zebrafish development[J]. Proc Natl Acad Sci USA, 2004, 101(35): 12792-12797. DOI: 10.1073/pnas.0403929101.
[73] GRAZIOTTO J J, INGLEHEARN C F, PACK M A, et al. Decreased levels of the RNA splicing factor Prpf3 in mice and zebrafish do not cause photoreceptor degeneration[J]. Invest Ophthalmol Vis Sci, 2008, 49(9): 3830-3838. DOI: 10.1167/iovs.07-1483.
[74] LINDER B, DILL H, HIRMER A, et al. Systemic splicing factor deficiency causes tissue-specific defects: a zebrafish model for retinitis pigmentosa[J]. Hum Mol Genet, 2011, 20(2): 368-377. DOI: 10.1093/hmg/ddq473.
[75] LIU Y, CHEN X, QIN B, et al. Knocking down Snrnp200 initiates demorphogenesis of rod photoreceptors in zebrafish[J]. J Ophthalmol, 2015, 2015: 816329. DOI: 10.1155/2015/816329.
[76] ZHANG T, BAI J S, ZHANG X Y, et al. SNRNP200 mutations cause autosomal dominant retinitis pigmentosa[J]. Front Med(Lausanne), 2021, 7: 588991. DOI: 10.3389/fmed.2020.588991.
[77] BUJAKOWSKA K, MAUBARET C, CHAKAROVA C F, et al. Study of gene-targeted mouse models of splicing factor gene Prpf31 implicated in human autosomal dominant retinitis pigmentosa(RP)[J]. Invest Ophthalmol Vis Sci, 2009, 50(12): 5927-5933. DOI: 10.1167/iovs.08-3275.
[78] GRAZIOTTO J J, FARKAS M H, BUJAKOWSKA K, et al. Three gene-targeted mouse models of RNA splicing factor RP show late-onset RPE and retinal degeneration[J]. Invest Ophthalmol Vis Sci, 2011, 52(1): 190-198. DOI: 10.1167/iovs.10-5194.
[79] FARKAS M H, LEW D S, SOUSA M E, et al. Mutations in pre-mRNA processing factors 3, 8, and 31 cause dysfunction of the retinal pigment epithelium[J]. Am J Pathol, 2014, 184(10): 2641-2652. DOI: 10.1016/j.ajpath.2014.06.026.
[80] YUAN L Y, KAWADA M, HAVLIOGLU N, et al. Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells[J]. J Neurosci, 2005, 25(3): 748-757. DOI: 10.1523/JNEUROSCI.2399-04.2005.
[81] KEVANY B M, PALCZEWSKI K. Phagocytosis of retinal rod and cone photoreceptors[J]. Physiology(Bethesda), 2010, 25(1): 8-15. DOI: 10.1152/physiol.00038.2009.