Skip to main content

Advertisement

SpringerLink
Log in

Retinal histopathology in eyes from patients with autosomal dominant retinitis pigmentosa caused by rhodopsin mutations

  • Basic Science
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the histopathology in donor eyes from patients with autosomal dominant retinitis pigmentosa (ADRP) caused by p.P23H, p.P347T and p.P347L rhodopsin ( RHO ) gene mutations.

Methods

Eyes from a 72-year-old male (donor 1), an 83-year-old female (donor 2), an 80-year-old female (donor 3), and three age-similar normal eyes were examined macroscopically, by scanning laser ophthalmoscopy and optical coherence tomography imaging. Perifoveal and peripheral pieces were processed for microscopy and immunocytochemistry with markers for photoreceptor cells.

Results

DNA analysis revealed RHO mutations c.68C>A (p.P23H) in donor 1, c.1040C>T (p.P347L) in donor 2 and c.1039C>A (p.P347T) in donor 3. Histology of the ADRP eyes showed retinas with little evidence of stratified nuclear layers in the periphery and a prominent inner nuclear layer present in the perifoveal region in the p.P23H and p.P347T eyes, while it was severely atrophic in the p.P347L eye. The p.P23H and p.P347T mutations cause a profound loss of rods in both the periphery and perifovea, while the p.P347L mutation displays near complete absence of rods in both regions. All three rhodopsin mutations caused a profound loss of cones in the periphery. The p.P23H and p.P347T mutations led to the presence of highly disorganized cones in the perifovea. However, the p.P347L mutation led to near complete absence of cones also in the perifovea.

Conclusions

Our results support clinical findings indicating that mutations affecting residue P347 develop more severe phenotypes than those affecting P23. Furthermore, our results indicate a more severe phenotype in the p.P347L retina as compared to the p.P347T retina.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Hamel C (2006) Retinitis pigmentosa. Orphanet J Rare Dis 1:40

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Sullivan LS, Bowne SJ, Birch DG, Hughbanks-Wheaton D, Heckenlively JR 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  PubMed Central  PubMed  Google Scholar 

  4. Sancho-Pelluz J, Arango-Gonzalez B, Kustermann S, Romero FJ, van Veen T et al (2008) Photoreceptor cell death mechanisms in inherited retinal degeneration. Mol Neurobiol 38:253–269

    Article  CAS  PubMed  Google Scholar 

  5. Malanson KM, Lem J (2009) Rhodopsin-mediated retinitis pigmentosa. Prog Mol Biol Transl Sci 88:1–31

    Article  CAS  PubMed  Google Scholar 

  6. Lewin AS, Rossmiller B, Mao H (2014) Gene augmentation for adRP mutations in RHO. Cold Spring Harb Perspect Med 4:a017400

    Article  PubMed Central  PubMed  Google Scholar 

  7. Kolb H, Gouras P (1974) Electron microscopic observations of human retinitis pigmentosa, dominantly inherited. Invest Ophthalmol 13:487–498

    CAS  PubMed  Google Scholar 

  8. Tucker GS, Jacobson SG (1988) Morphological findings in retinitis pigmentosa with early diffuse rod dysfunction. Retina 8:30–41

    Article  CAS  PubMed  Google Scholar 

  9. Li ZY, Jacobson SG, Milam AH (1994) Autosomal dominant retinitis pigmentosa caused by the threonine-17-methionine rhodopsin mutation: retinal histopathology and immunocytochemistry. Exp Eye Res 58:397–408

    Article  CAS  PubMed  Google Scholar 

  10. Milam AH, Li ZY, Cideciyan AV, Jacobson SG (1996) Clinicopathologic effects of the Q64ter rhodopsin mutation in retinitis pigmentosa. Invest Ophthalmol Vis Sci 37:753765

    Google Scholar 

  11. Fariss RN, Apte SS, Luthert PJ, Bird AC, Milam AH (1998) Accumulation of tissue inhibitor of metalloproteinases-3 in human eyes with Sorsby’s fundus dystrophy or retinitis pigmentosa. Br J Ophthalmol 82:1329–1334

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. John SK, Smith JE, Aguirre GD, Milam AH (2000) Loss of cone molecular markers in rhodopsin-mutant human retinas with retinitis pigmentosa. Mol Vis 6:204–215

    CAS  PubMed  Google Scholar 

  13. To K, Adamian M, Berson EL (2004) Histologic study of retinitis pigmentosa due to a mutation in the RP13 gene (PRPC8): comparison with rhodopsin Pro23His, Cys110Arg, and Glu181Lys. Am J Ophthalmol 137:946–948

    Article  CAS  PubMed  Google Scholar 

  14. To K, Adamian M, Dryja TP, Berson EL (2000) Retinal histopathology of an autopsy eye with advanced retinitis pigmentosa in a family with rhodopsin Glu181Lys. Am J Ophthalmol 130:790–792

    Article  CAS  PubMed  Google Scholar 

  15. To K, Adamian M, Dryja TP, Berson EL (2002) Histopathologic study of variation in severity of retinitis pigmentosa due to the dominant rhodopsin mutation Pro23His. Am J Ophthalmol 134:290–293

    Article  CAS  PubMed  Google Scholar 

  16. Berson EL, Rosner B, Sandberg MA, Dryja TP (1991) Ocular findings in patients with autosomal dominant retinitis pigmentosa and a rhodopsin gene defect (Pro-23-His). Arch Ophthalmol 109:92–101

    Article  CAS  PubMed  Google Scholar 

  17. Fernandez-San Jose P, Blanco-Kelly F, Corton M, Trujillo-Tiebas MJ, Gimenez A et al (2015) Prevalence of Rhodopsin mutations in autosomal dominant Retinitis Pigmentosa in Spain: clinical and analytical review in 200 families. Acta Ophthalmol 93:e38–44

    Article  CAS  PubMed  Google Scholar 

  18. Rakoczy EP, Kiel C, McKeone R, Stricher F, Serrano L (2011) Analysis of disease-linked rhodopsin mutations based on structure, function, and protein stability calculations. J Mol Biol 405:584–606

    Article  CAS  PubMed  Google Scholar 

  19. Berson EL, Rosner B, Sandberg MA, Weigel-DiFranco C, Dryja TP (1991) Ocular findings in patients with autosomal dominant retinitis pigmentosa and rhodopsin, proline-347- leucine. Am J Ophthalmol 111:614–623

    Article  CAS  PubMed  Google Scholar 

  20. Oh KT, Longmuir R, Oh DM, Stone EM, Kopp K et al (2003) Comparison of the clinical expression of retinitis pigmentosa associated with rhodopsin mutations at codon 347 and codon 23. Am J Ophthalmol 136:306–313

    Article  CAS  PubMed  Google Scholar 

  21. Aleman TS, Cideciyan AV, Sumaroka A, Windsor EA, Herrera W et al (2008) Retinal laminar architecture in human retinitis pigmentosa caused by Rhodopsin gene mutations. Invest Ophthalmol Vis Sci 49:1580–1590

    Article  PubMed Central  PubMed  Google Scholar 

  22. Bagheri N, Bell BA, Bonilha VL, Hollyfield JG (2012) Imaging human postmortem eyes with SLO and OCT. Adv Exp Med Biol 723:479–488

    Article  CAS  PubMed  Google Scholar 

  23. Bonilha VL, Rayborn ME, Bell BA, Marino MJ, Fishman GA, et al (2014) Retinal histopathology in eyes from a patient with stargardt disease caused by compound heterozygous ABCA4 mutations. Ophthalmic Genet 1–11

  24. Crow JF (2000) The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1:40–47

    Article  CAS  PubMed  Google Scholar 

  25. Dikshit M, Agarwal R (2001) Mutation analysis of codons 345 and 347 of rhodopsin gene in Indian retinitis pigmentosa patients. J Genet 80:111–116

    Article  CAS  PubMed  Google Scholar 

  26. Sung CH, Davenport CM, Hennessey JC, Maumenee IH, Jacobson SG et al (1991) Rhodopsin mutations in autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A 88:6481–6485

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Mendes HF, van der Spuy J, Chapple JP, Cheetham ME (2005) Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy. Trends Mol Med 11:177–185

    Article  CAS  PubMed  Google Scholar 

  28. Sandberg MA, Weigel-DiFranco C, Dryja TP, Berson EL (1995) Clinical expression correlates with location of rhodopsin mutation in dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci 36:1934–1942

    CAS  PubMed  Google Scholar 

  29. Pannarale MR, Grammatico B, Iannaccone A, Forte R, DeBernardo C et al (1996) Autosomal-dominant retinitis pigmentosa associated with an Arg-135-Trp point mutation of the rhodopsin gene. Clinical features and longitudinal observations. Ophthalmology 103:1443–1452

    Article  CAS  PubMed  Google Scholar 

  30. Mazelova J, Astuto-Gribble L, Inoue H, Tam BM, Schonteich E et al (2009) Ciliary targeting motif VxPx directs assembly of a trafficking module through Arf4. EMBO J 28:183–192

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Tam BM, Moritz OL, Hurd LB, Papermaster DS (2000) Identification of an outer segment targeting signal in the COOH terminus of rhodopsin using transgenic Xenopus laevis. J Cell Biol 151:1369–1380

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Deretic D, Williams AH, Ransom N, Morel V, Hargrave PA et al (2005) Rhodopsin C terminus, the site of mutations causing retinal disease, regulates trafficking by binding to ADP-ribosylation factor 4 (ARF4). Proc Natl Acad Sci U S A 102:3301–3306

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Tam BM, Xie G, Oprian DD, Moritz OL (2006) Mislocalized rhodopsin does not require activation to cause retinal degeneration and neurite outgrowth in Xenopus laevis. J Neurosci 26:203–209

    Article  CAS  PubMed  Google Scholar 

  34. Tso MO, Li WW, Zhang C, Lam TT, Hao Y et al (1997) A pathologic study of degeneration of the rod and cone populations of the rhodopsin Pro347Leu transgenic pigs. Trans Am Ophthalmol Soc 95:467–479, discussion 479–483

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Kondo M, Sakai T, Komeima K, Kurimoto Y, Ueno S et al (2009) Generation of a transgenic rabbit model of retinal degeneration. Invest Ophthalmol Vis Sci 50:13711377

    Article  Google Scholar 

  36. Marc RE, Jones BW, Anderson JR, Kinard K, Marshak DW et al (2007) Neural reprogramming in retinal degeneration. Invest Ophthalmol Vis Sci 48:3364–3371

    Article  PubMed Central  PubMed  Google Scholar 

  37. Jones BW, Kondo M, Terasaki H, Watt CB, Rapp K et al (2011) Retinal remodeling in the Tg P347L rabbit, a large-eye model of retinal degeneration. J Comp Neurol 519:27132733

    Article  Google Scholar 

  38. Humayun MS, Weiland JD, Fujii GY, Greenberg R, Williamson R et al (2003) Visual perception in a blind subject with a chronic microelectronic retinal prosthesis. Vision Res 43:2573–2581

    Article  PubMed  Google Scholar 

  39. Zrenner E, Bartz-Schmidt KU, Benav H, Besch D, Bruckmann A et al (2011) Subretinal electronic chips allow blind patients to read letters and combine them to words. Proc Biol Sci 278:1489–1497

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Peter MacLeish (Morehouse School of Medicine, Atlanta, GA) for providing us with the antibody to cone arrestin (7G6). Pedigree courtesy of the Berman-Gund Lab (Massachusetts Eye and Ear Infirmary, Boston, MA). This work was supported by The Foundation Fighting Blindness Histopathology Grant F-OH01-1102-0231 (JGH), Research Center Grants from The Foundation Fighting Blindness (JGH), Research to Prevent Blindness Unrestricted Grant and National Institutes of Health grant R01EY014240-08 (JGH) and the Llura and Gordon Gund Foundation.

Conflict of interest statement

The authors declare that they have no financial interest in the subject matter or materials discussed in this manuscript.

Author information

Authors and Affiliations

  1. Cole Eye Institute, Cleveland Clinic, Ophthalmic Research - i31, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Vera L. Bonilha, Mary E. Rayborn, Brent A. Bell, Meghan J. Marino, Craig D. Beight, Gayle J. Pauer, Elias I. Traboulsi, Joe G. Hollyfield & Stephanie A. Hagstrom

  2. Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA

    Vera L. Bonilha, Elias I. Traboulsi, Joe G. Hollyfield & Stephanie A. Hagstrom

Authors
  1. Vera L. Bonilha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mary E. Rayborn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brent A. Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meghan J. Marino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Craig D. Beight
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gayle J. Pauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elias I. Traboulsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joe G. Hollyfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephanie A. Hagstrom
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vera L. Bonilha.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bonilha, V.L., Rayborn, M.E., Bell, B.A. et al. Retinal histopathology in eyes from patients with autosomal dominant retinitis pigmentosa caused by rhodopsin mutations. Graefes Arch Clin Exp Ophthalmol 253, 2161–2169 (2015). https://doi.org/10.1007/s00417-015-3099-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-015-3099-7

Keywords

Search

Navigation