Skip to main content
SpringerLink
Log in

Retinal Pigment Epithelial Cells: The Unveiled Component in the Etiology of Prpf Splicing Factor-Associated Retinitis Pigmentosa

  • Conference paper
  • First Online:
Retinal Degenerative Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1185))

Abstract

Pre-mRNA splicing is a critical step in RNA processing in all eukaryotic cells. It consists of introns removal and requires the assembly of a large RNA-protein complex called the spliceosome. This complex of small nuclear ribonucleoproteins is associated with accessory proteins from the pre-mRNA processing factor (PRPF) family. Mutations in different splicing factor-encoding genes were identified in retinitis pigmentosa (RP) patients. A surprising feature of these ubiquitous factors is that the outcome of their alteration is restricted to the retina. Because of their high metabolic demand, most studies focused on photoreceptors dysfunction and associated degeneration. However, cells from the retinal pigment epithelium (RPE) are also crucial to maintaining retinal homeostasis and photoreceptor function. Moreover, mutations in RPE-specific genes are associated with some RP cases. Indeed, we identified major RPE defects in Prpf31-mutant mice: circadian rhythms of both photoreceptor outer segments (POS) phagocytosis and retinal adhesion were attenuated or lost, leading to ultrastructural anomalies and vacuoles. Taken together, our published and ongoing data suggest that (1) similar molecular events take place in human and mouse cells and (2) these functional defects generate various stress processes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Audo I, Bujakowska K, Mohand-Saïd S et al (2010) Prevalence and novelty of PRPF31 mutations in French autosomal dominant rod-cone dystrophy patients and a review of published reports. BMC Med Genet 11:145

    Article  Google Scholar 

  • Ben-Shabat S, Itagaki Y, Jockusch S et al (2002) Formation of a nonaoxirane from A2E, a lipofuscin fluorophore related to macular degeneration, and evidence of singlet oxygen involvement. Angew Chem Int Ed Engl 41:814–817

    Article  CAS  Google Scholar 

  • Bourne MC, Campbell DA, Tansley K (1938) Hereditary degeneration of the rat retina. Br J Ophthalmol 22:613–623

    Article  CAS  Google Scholar 

  • Bujakowska K, Maubaret C, Chakarova CF et al (2009) Study of gene-targeted mouse models of splicing factor gene Prpf31 implicated in human autosomal dominant retinitis pigmentosa (RP). Invest Opthalmol Vis Sci 50:5927

    Article  Google Scholar 

  • Burstyn-Cohen T, Lew ED, Través PG et al (2012) Genetic dissection of TAM receptor-ligand interaction in retinal pigment epithelial cell phagocytosis. Neuron 76:1123–1132

    Article  CAS  Google Scholar 

  • Buskin A, Zhu L, Chichagova V et al (2018) Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nat Commun 9:4234

    Article  Google Scholar 

  • Cao H, Wu J, Lam S et al (2011) Temporal and tissue specific regulation of RP-associated splicing factor genes PRPF3, PRPF31 and PRPC8--implications in the pathogenesis of RP. PLoS One 6:e15860

    Article  CAS  Google Scholar 

  • Chakarova CF, Hims MM, Bolz H et al (2002) Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa. Hum Mol Genet 11:87–92

    Article  CAS  Google Scholar 

  • Chen X, Liu Y, Sheng X et al (2014) PRPF4 mutations cause autosomal dominant retinitis pigmentosa. Hum Mol Genet 23:2926–2939

    Article  CAS  Google Scholar 

  • D’Cruz PM, Yasumura D, Weir J et al (2000) Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 9:645–651

    Article  Google Scholar 

  • Dowling JE, Sidman RL (1962) Inherited retinal dystrophy in the rat. J Cell Biol 14:73–109

    Article  CAS  Google Scholar 

  • Farkas MH, Lew DS, Sousa ME et al (2014) Mutations in pre-mRNA processing factors 3, 8, and 31 cause dysfunction of the retinal pigment epithelium. Am J Pathol 184:2641–2652

    Article  CAS  Google Scholar 

  • Graziotto JJ, Farkas MH, Bujakowska K et al (2011) Three gene-targeted mouse models of RNA splicing factor RP show late-onset RPE and retinal degeneration. Invest Opthalmol Vis Sci 52:190

    Article  CAS  Google Scholar 

  • Haigis MC, Yankner BA (2010) The aging stress response. Mol Cell 40:333–344

    Article  CAS  Google Scholar 

  • Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809

    Article  CAS  Google Scholar 

  • LaVail MM (1976) Rod outer segment disk shedding in rat retina: relationship to cyclic lighting. Science 194:1071–1074

    Article  CAS  Google Scholar 

  • Law A-L, Parinot C, Chatagnon J et al (2015) Cleavage of Mer tyrosine kinase (MerTK) from the cell surface contributes to the regulation of retinal phagocytosis. J Biol Chem 290:4941–4952

    Article  CAS  Google Scholar 

  • Maita H, Kitaura H, Keen TJ et al (2004) PAP-1, the mutated gene underlying the RP9 form of dominant retinitis pigmentosa, is a splicing factor. Exp Cell Res 300:283–296

    Article  CAS  Google Scholar 

  • Makarova OV, Makarov EM, Liu S et al (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

    Article  CAS  Google Scholar 

  • McKie AB, McHale JC, Keen TJ et al (2001) Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13). Hum Mol Genet 10:1555–1562

    Article  CAS  Google Scholar 

  • Mordes D, Yuan L, Xu L et al (2007) Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa. Neurobiol Dis 26:291–300

    Article  CAS  Google Scholar 

  • Nandrot E, Dufour EM, Provost AC et al (2000) Homozygous deletion in the coding sequence of the c-mer gene in RCS rats unravels general mechanisms of physiological cell adhesion and apoptosis. Neurobiol Dis 7:586–599

    Article  CAS  Google Scholar 

  • Nandrot EF, Kim Y, Brodie SE et al (2004) Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking αvβ5 integrin. J Exp Med 200:1539–1545

    Article  CAS  Google Scholar 

  • Nandrot EF, Anand M, Almeida D et al (2007) Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis. Proc Natl Acad Sci 104:12005–12010

    Article  CAS  Google Scholar 

  • Nandrot EF, Silva KE, Scelfo C et al (2012) Retinal pigment epithelial cells use a MerTK-dependent mechanism to limit the phagocytic particle binding activity of αvβ5 integrin. Biol Cell 104:326–341

    Article  CAS  Google Scholar 

  • Schaffert N, Hossbach M, Heintzmann R et al (2004) RNAi knockdown of hPrp31 leads to an accumulation of U4/U6 di-snRNPs in Cajal bodies. EMBO J 23:3000–3009

    Article  CAS  Google Scholar 

  • Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–881

    Article  CAS  Google Scholar 

  • Sullivan LS, Bowne SJ, Birch DG et al (2006) Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Invest Ophthalmol Vis Sci 47:3052–3064

    Article  Google Scholar 

  • Tanackovic G, Rivolta C (2009) PRPF31 alternative splicing and expression in human retina. Ophthalmic Genet 30:76–83

    Article  CAS  Google Scholar 

  • Tanackovic G, Ransijn A, Ayuso C et al (2011) A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa. Am J Hum Genet 88:643–649

    Article  CAS  Google Scholar 

  • Vithana EN, Abu-Safieh L, Allen MJ et al (2001) A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol Cell 8:375–381

    Article  CAS  Google Scholar 

  • 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 44:4204–4209

    Article  Google Scholar 

  • Winkler BS (2008) An hypothesis to account for the renewal of outer segments in rod and cone photoreceptor cells: renewal as a surrogate antioxidant. Invest Ophthalmol Vis Sci 49:3259–3261

    Article  Google Scholar 

  • Yin J, Brocher J, Fischer U et al (2011) Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for retinitis pigmentosa. Mol Neurodegener 6:56

    Article  CAS  Google Scholar 

  • Young RW, Bok D (1969) Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol 42:392–403

    Article  CAS  Google Scholar 

  • Yuan L, Kawada M, Havlioglu N et al (2005) Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells. J Neurosci 25:748–757

    Article  CAS  Google Scholar 

  • Zhao C, Bellur DL, Lu S et al (2009) Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs. Am J Hum Genet 85:617–627

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Therapeutics Department, Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France

    Abdallah Hamieh & Emeline F. Nandrot

Authors
  1. Abdallah Hamieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emeline F. Nandrot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emeline F. Nandrot .

Editor information

Editors and Affiliations

  1. Department of Ophthalmology, Duke University, Durham, NC, USA

    Catherine Bowes Rickman

  2. Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland

    Christian Grimm

  3. Health Sciences Center, University of Oklahoma, Oklahoma City, OK, USA

    Robert E. Anderson

  4. Ophthalmology, University of Florida, Gainesville, FL, USA

    John D. Ash

  5. Beckman Vision Center, University of California, San Francisco, San Fancisco, CA, USA

    Matthew M. LaVail

  6. Department of Ophthalmology, Case Western Reserve University, Cleveland, OH, USA

    Joe G. Hollyfield

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this paper

Check for updates. Verify currency and authenticity via CrossMark

Cite this paper

Hamieh, A., Nandrot, E.F. (2019). Retinal Pigment Epithelial Cells: The Unveiled Component in the Etiology of Prpf Splicing Factor-Associated Retinitis Pigmentosa. In: Bowes Rickman, C., Grimm, C., Anderson, R., Ash, J., LaVail, M., Hollyfield, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 1185. Springer, Cham. https://doi.org/10.1007/978-3-030-27378-1_37

Download citation

Publish with us

Policies and ethics

Search

Navigation