PRPF31 is the gene coding for the splicing factor hPRP31. It is essential for the formation of the spliceosome hPRP31 is associated with the U4/U6 di-snRNP and interacts with another splicing factor, hPRP6, to form the U4/U6-U5 tri-snRNP. It has been shown that when hPRP31 is knocked down by RNAi, U4/U6 di-snRNPs accumulate in the Cajal bodies and the U4/U6-U5 tri-snRNP cannot form.[2]
PRPF31 is recruited to introns following the attachment of U4 and U6 RNAs and the 15.5K protein NHP2L1. The addition of PRPF31 is crucial for the transition of the spliceosomal complex to the activated state.[3]
Clinical significance
A mutation in PRPF31 is one of 4 known mutations in splicing factors which are known to cause retinitis pigmentosa. The first mutation in PRPF31 was discovered by Vithana et al. in 2001.[1] Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies characterized by a progressive degeneration of photoreceptors, eventually resulting in severe visual impairment.[4]
Inheritance
Mutations in PRPF31 are inherited in an autosomal dominant manner, accounting for 2.5% of cases of autosomal dominantretinitis pigmentosa (adRP) in a mixed UK population.[5] However, the inheritance pattern of PRPF31 mutations is atypical of dominant inheritance, showing the phenomenon of partial penetrance, whereby a dominant mutations appear to "skip" generations. This is thought to be due to the presence of two wild type alleles, a high-expressivity allele and a low-expressivity allele. If a patient has a mutant allele and a high-expressivity allele, they do not show disease phenotype. If a patient has a mutant allele and a low-expressivity allele, the residual level of protein falls beneath the threahold for normal function, and so they do show disease phenotype. The inheritance pattern of PRPF31 can therefore be thought of as a variation of haploinsufficiency. This variant of haploinsufficiency is only seen in two other human diseases: Erythropoietic protoporphyria, caused by mutations in the FECH gene; and hereditary elliptocytosis, caused by mutations in the spectrin gene.[6][7]
References
↑ 1.01.1Vithana EN, Abu-Safieh L, Allen MJ, Carey A, Papaioannou M, Chakarova C, Al-Maghtheh M, Ebenezer ND, Willis C, Moore AT, Bird AC, Hunt DM, Bhattacharya SS (August 2001). "A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11)". Mol. Cell. 8 (2): 375–81. doi:10.1016/S1097-2765(01)00305-7. PMID11545739.
↑Liu S, Li P, Dybkov O, Nottrott S, Hartmuth K, Lührmann R, Carlomagno T, Wahl MC (April 2007). "Binding of the human Prp31 Nop domain to a composite RNA-protein platform in U4 snRNP". Science. 316 (5821): 115–20. doi:10.1126/science.1137924. PMID17412961.
↑Waseem NH, Vaclavik V, Webster A, Jenkins SA, Bird AC, Bhattacharya SS (March 2007). "Mutations in the gene coding for the pre-mRNA splicing factor, PRPF31, in patients with autosomal dominant retinitis pigmentosa". Investigative Ophthalmology & Visual Science. 48 (3): 1330–4. doi:10.1167/iovs.06-0963. PMID17325180.
↑Randon J, Boulanger L, Marechal J, Garbarz M, Vallier A, Ribeiro L, Tamagnini G, Dhermy D, Delaunay J (Nov 1994). "A variant of spectrin low-expression allele alpha LELY carrying a hereditary elliptocytosis mutation in codon 28". Br J Haematol. 88 (3): 534–40. doi:10.1111/j.1365-2141.1994.tb05070.x. PMID7819065.
↑Gouya L, Puy H, Lamoril J, Da Silva V, Grandchamp B, Nordmann Y, Deybach JC (Jun 1998). "Inheritance in erythropoietic protoporphyria: a common wild-type ferrochelatase allelic variant with low expression accounts for clinical manifestation". Am J Hum Genet. 93 (6): 2150–10. PMID10068685.
Further reading
Tarizzo ML (1975). "The World Health Organization and the prevention of blindness". Transactions. Section on Ophthalmology. American Academy of Ophthalmology and Otolaryngology. 79 (3 Pt 2): OP453–6. PMID1154573.
al-Maghtheh M, Inglehearn CF, Keen TJ, et al. (1994). "Identification of a sixth locus for autosomal dominant retinitis pigmentosa on chromosome 19". Hum. Mol. Genet. 3 (2): 351–4. doi:10.1093/hmg/3.2.351. PMID8004108.
Martínez-Gimeno M, Gamundi MJ, Hernan I, et al. (2003). "Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa". Invest. Ophthalmol. Vis. Sci. 44 (5): 2171–7. doi:10.1167/iovs.02-0871. PMID12714658.
Scanlan MJ, Gout I, Gordon CM, et al. (2003). "Humoral immunity to human breast cancer: antigen definition and quantitative analysis of mRNA expression". Cancer Immun. 1: 4. PMID12747765.
Reuter TY, Medhurst AL, Waisfisz Q, et al. (2003). "Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport". Exp. Cell Res. 289 (2): 211–21. doi:10.1016/S0014-4827(03)00261-1. PMID14499622.
Vithana EN, Abu-Safieh L, Pelosini L, et al. (2003). "Expression of PRPF31 mRNA in patients with autosomal dominant retinitis pigmentosa: a molecular clue for incomplete penetrance?". Invest. Ophthalmol. Vis. Sci. 44 (10): 4204–9. doi:10.1167/iovs.03-0253. PMID14507862.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID14702039.
Grimwood J, Gordon LA, Olsen A, et al. (2004). "The DNA sequence and biology of human chromosome 19". Nature. 428 (6982): 529–35. doi:10.1038/nature02399. PMID15057824.
Xia K, Zheng D, Pan Q, et al. (2004). "A novel PRPF31 splice-site mutation in a Chinese family with autosomal dominant retinitis pigmentosa". Mol. Vis. 10: 361–5. PMID15162096.
