Purpose This study was intended to identify the disease causing genes in a large Chinese family with autosomal dominant retinitis pigmentosa and macular degeneration. Methods A genome scan analysis was conducted in this family for disease gene preliminary mapping. Snapshot analysis of selected SNPs for two-point LOD score analysis for candidate gene filter. Candidate gene PRPF31 whole exons' sequencing was executed to identify mutations. Results A novel nonsense mutation caused by an insertion was found in PRPF31 gene. All the 19 RP patients in 1085 family are carrying this heterozygous nonsense mutation. The nonsense mutation is in PRPF31 gene exon9 at chr19:54629961-54629961, inserting nucleotide “A” that generates the coding protein frame shift from p.307 and early termination at p.322 in the snoRNA binding domain (NOP domain). Conclusion This report is the first to associate PRPF31 gene's nonsense mutation and adRP and JMD. Our findings revealed that PRPF31 can lead to different clinical phenotypes in the same family, resulting either in adRP or syndrome of adRP and JMD. We believe our identification of the novel “A” insertion mutation in exon9 at chr19:54629961-54629961 in PRPF31 can provide further genetic evidence for clinical test for adRP and JMD.
Golovleva I, Kohn L, Burstedt M, Daiger S, Sandgren O (2010) Mutation spectra in autosomal dominant and recessive retinitis pigmentosa in northern Sweden. Adv Exp Med Biol 664: 255–262.
Rossi S, Testa F, Attanasio M, Orrico A, de Benedictis A, et al. (2012) Subretinal Fibrosis in Stargardt's Disease with Fundus Flavimaculatus and ABCA4 Gene Mutation. Case Report Ophthalmol 3: 410–417.
[6]
Mullins RF, Kuehn MH, Radu RA, Enriquez GS, East JS, et al. (2012) Autosomal recessive retinitis pigmentosa due to ABCA4 mutations: clinical, pathologic, and molecular characterization. Invest Ophthalmol Vis Sci 53: 1883–1894.
[7]
Rudolph G, Kalpadakis P, Haritoglou C, Rivera A, Weber BH (2002) Mutations in the ABCA4 gene in a family with Stargardt's disease and retinitis pigmentosa (STGD1/RP19). Klin Monbl Augenheilkd 219: 590–596.
[8]
Maia-Lopes S, Castelo-Branco M, Silva E, Villaverde C, Aguirre J, et al. (2008) Gene symbol: BEST1. Disease: Best macular dystrophy. Hum Genet 123: 110.
[9]
Davidson AE, Millar ID, Urquhart JE, Burgess-Mullan R, Shweikh Y, et al. (2009) Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. Am J Hum Genet 85: 581–592.
[10]
Wada Y, Abe T, Itabashi T, Sato H, Kawamura M, et al. (2003) Autosomal dominant macular degeneration associated with 208delG mutation in the FSCN2 gene. Arch Ophthalmol 121: 1613–1620.
[11]
Gamundi MJ, Hernan I, Maseras M, Baiget M, Ayuso C, et al. (2005) Sequence variations in the retinal fascin FSCN2 gene in a Spanish population with autosomal dominant retinitis pigmentosa or macular degeneration. Mol Vis 11: 922–928.
[12]
Khani SC, Karoukis AJ, Young JE, Ambasudhan R, Burch T, et al. (2003) Late-onset autosomal dominant macular dystrophy with choroidal neovascularization and nonexudative maculopathy associated with mutation in the RDS gene. Invest Ophthalmol Vis Sci 44: 3570–3577.
[13]
Lim KP, Yip SP, Cheung SC, Leung KW, Lam ST, et al. (2009) Novel PRPF31 and PRPH2 mutations and co-occurrence of PRPF31 and RHO mutations in Chinese patients with retinitis pigmentosa. Arch Ophthalmol 127: 784–790.
[14]
Permanyer J, Navarro R, Friedman J, Pomares E, Castro-Navarro J, et al. (2010) Autosomal recessive retinitis pigmentosa with early macular affectation caused by premature truncation in PROM1. Invest Ophthalmol Vis Sci 51: 2656–2663.
[15]
Michaelides M, Gaillard MC, Escher P, Tiab L, Bedell M, et al. (2010) The PROM1 mutation p. R373C causes an autosomal dominant bull's eye maculopathy associated with rod, rod-cone, and macular dystrophy. Invest Ophthalmol Vis Sci 51: 4771–4780.
[16]
Chen LJ, Lai TY, Tam PO, Chiang SW, Zhang X, et al. (2010) Compound heterozygosity of two novel truncation mutations in RP1 causing autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci 51: 2236–2242.
[17]
Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, et al. (1998) Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A 95: 3088–3093.
[18]
Gollapalli DR, Rando RR (2004) The specific binding of retinoic acid to RPE65 and approaches to the treatment of macular degeneration. Proc Natl Acad Sci U S A 101: 10030–10035.
[19]
Moiseyev G, Nikolaeva O, Chen Y, Farjo K, Takahashi Y, et al. (2010) Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease. Proc Natl Acad Sci U S A 107: 17551–17556.
[20]
Ayyagari R, Demirci FY, Liu J, Bingham EL, Stringham H, et al. (2002) X-linked recessive atrophic macular degeneration from RPGR mutation. Genomics 80: 166–171.
[21]
Fujita R, Swaroop A (1996) RPGR: part one of the X-linked retinitis pigmentosa story. Mol Vis 2: 4.
[22]
al-Maghtheh M, Inglehearn CF, Keen TJ, Evans K, Moore AT, et al. (1994) Identification of a sixth locus for autosomal dominant retinitis pigmentosa on chromosome 19. Hum Mol Genet 3: 351–354.
[23]
Al-Maghtheh M, Vithana E, Tarttelin E, Jay M, Evans K, et al. (1996) Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11) and association with a unique bimodal expressivity phenotype. Am J Hum Genet 59: 864–871.
[24]
Abu-Safieh L, Vithana EN, Mantel I, Holder GE, Pelosini L, et al. (2006) A large deletion in the adRP gene PRPF31: evidence that haploinsufficiency is the cause of disease. Mol Vis 12: 384–388.
[25]
Sullivan LS, Bowne SJ, Seaman CR, Blanton SH, Lewis RA, et al. (2006) Genomic rearrangements of the PRPF31 gene account for 2.5% of autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci 47: 4579–4588.
[26]
Martinez-Gimeno M, Gamundi MJ, Hernan I, Maseras M, Milla E, 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: 2171–2177.
[27]
Wang L, Ribaudo M, Zhao K, Yu N, Chen Q, et al. (2003) Novel deletion in the pre-mRNA splicing gene PRPF31 causes autosomal dominant retinitis pigmentosa in a large Chinese family. Am J Med Genet A 121A: 235–239.
[28]
Lu SS, Zhao C, Cui Y, Li ND, Zhang XM, et al. (2005) [Novel splice-site mutation in the pre-mRNA splicing gene PRPF31 in a Chinese family with autosomal dominant retinitis pigmentosa]. Zhonghua Yan Ke Za Zhi 41: 305–311.
[29]
Wilkie SE, Morris KJ, Bhattacharya SS, Warren MJ, Hunt DM (2006) A study of the nuclear trafficking of the splicing factor protein PRPF31 linked to autosomal dominant retinitis pigmentosa (ADRP). Biochim Biophys Acta 1762: 304–311.
[30]
Taira K, Nakazawa M, Sato M (2007) Mutation c. 1142 del G in the PRPF31 gene in a family with autosomal dominant retinitis pigmentosa (RP11) and its implications. Jpn J Ophthalmol 51: 45–48.
[31]
Makarova OV, Makarov EM, Liu S, Vornlocher HP, Luhrmann R (2002) 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 21: 1148–1157.
[32]
Deery EC, Vithana EN, Newbold RJ, Gallon VA, Bhattacharya SS, et al. (2002) Disease mechanism for retinitis pigmentosa (RP11) caused by mutations in the splicing factor gene PRPF31. Hum Mol Genet 11: 3209–3219.
[33]
Talmud PJ, Converse C, Krul E, Huq L, McIlwaine GG, et al. (1992) A novel truncated apolipoprotein B (apo B55) in a patient with familial hypobetalipoproteinemia and atypical retinitis pigmentosa. Clin Genet 42: 62–70.
[34]
Vithana EN, Abu-Safieh L, Pelosini L, Winchester E, Hornan D, 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: 4204–4209.
[35]
Tanackovic G, Rivolta C (2009) PRPF31 alternative splicing and expression in human retina. Ophthalmic Genet 30: 76–83.
[36]
Yin J, Brocher J, Fischer U, Winkler C (2011) Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa. Mol Neurodegener 6: 56.
[37]
Liu S, Li P, Dybkov O, Nottrott S, Hartmuth K, et al. (2007) Binding of the human Prp31 Nop domain to a composite RNA-protein platform in U4 snRNP. Science 316: 115–120.
