Skip to main content

Advertisement

SpringerLink
Log in

Novel REEP6 gene mutation associated with autosomal recessive retinitis pigmentosa

  • Clinical Case Report
  • Published:
Documenta Ophthalmologica Aims and scope Submit manuscript

Abstract

Purpose

This study reports the ophthalmic and genetic findings of a Cameroonian patient with autosomal recessive retinitis pigmentosa (arRP) caused by a novel Receptor Expression Enhancing Protein 6 (REEP6) homozygous mutation.

Patient and methods

A 33-year-old man underwent comprehensive ophthalmic examinations, including visual acuity measurements, dilated fundus imaging, electroretinography (ERG), and spectral-domain optical coherence tomography (SD-OCT). Short-wavelength fundus autofluorescence (SW-AF) and near-infrared fundus autofluorescence (NIR-AF) were also evaluated. Whole exome sequencing (WES) was used to identify potential pathogenic variants.

Results

Fundus examination revealed typical RP findings with additional temporal ten micron yellow dots. SD-OCT imaging revealed cystoid macular edema and perifoveal outer retinal atrophy with centrally preserved inner segment ellipsoid zone (EZ) bands. Hyperreflective spots were seen in the inner retinal layers. On SW-AF images, a hypoautofluorescent area in the perifoveal area was observed. NIR-AF imaging revealed an irregularly shaped hyperautofluorescent ring. His visual acuity was mildly affected. ERG showed undetectable rod responses and intact cone responses. Genetic testing via WES revealed a novel homozygous mutation (c.295G>A, p.Glu99Lys) in the gene encoding REEP6, which is predicted to alter the charge in the transmembrane helix.

Conclusions

This report is not only the first description of a Cameroonian patient with arRP associated with a REEP6 mutation, but also this particular genetic alteration. Substitution of p.Glu99Lys in REEP6 likely disrupts the interactions between REEP6 and the ER membrane. NIR-AF imaging may be particularly useful for assessing functional photoreceptor cells and show an “avocado” pattern of hyperautofluorescence in patients with the REEP6 mutation.

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

Similar content being viewed by others

References

  1. Verbakel SK, van Huet RAC, Boon CJF, den Hollander AI, Collin RWJ, Klaver CCW, Hoyng CB, Roepman R, Klevering BJ (2018) Non-syndromic retinitis pigmentosa. Prog Retin Eye Res 66:157–186. https://doi.org/10.1016/j.preteyeres.2018.03.005

    Article  PubMed  Google Scholar 

  2. Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368(9549):1795–1809. https://doi.org/10.1016/S0140-6736(06)69740-7

    Article  CAS  PubMed  Google Scholar 

  3. Hamel C (2006) Retinitis pigmentosa. Orphanet J Rare Dis 1:40. https://doi.org/10.1186/1750-1172-1-40

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bhatia S, Goyal S, Singh IR, Singh D, Vanita V (2018) A novel mutation in the PRPF31 in a North Indian adRP family with incomplete penetrance. Doc Ophthalmol 137(2):103–119. https://doi.org/10.1007/s10633-018-9654-x

    Article  PubMed  Google Scholar 

  5. Bunker CH, Berson EL, Bromley WC, Hayes RP, Roderick TH (1984) Prevalence of retinitis pigmentosa in Maine. Am J Ophthalmol 97(3):357–365

    Article  CAS  Google Scholar 

  6. Veleri S, Nellissery J, Mishra B, Manjunath SH, Brooks MJ, Dong L, Nagashima K, Qian H, Gao C, Sergeev YV, Huang XF, Qu J, Lu F, Cideciyan AV, Li T, Jin ZB, Fariss RN, Ratnapriya R, Jacobson SG, Swaroop A (2017) REEP6 mediates trafficking of a subset of Clathrin-coated vesicles and is critical for rod photoreceptor function and survival. Hum Mol Genet 26(12):2218–2230. https://doi.org/10.1093/hmg/ddx111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Arno G, Agrawal SA, Eblimit A, Bellingham J, Xu M, Wang F, Chakarova C, Parfitt DA, Lane A, Burgoyne T, Hull S, Carss KJ, Fiorentino A, Hayes MJ, Munro PM, Nicols R, Pontikos N, Holder GE, Ukirdc AC, Raymond FL, Moore AT, Plagnol V, Michaelides M, Hardcastle AJ, Li Y, Cukras C, Webster AR, Cheetham ME, Chen R (2016) Mutations in REEP6 cause autosomal-recessive retinitis pigmentosa. Am J Hum Genet 99(6):1305–1315. https://doi.org/10.1016/j.ajhg.2016.10.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mejecase C, Mohand-Said S, El Shamieh S, Antonio A, Condroyer C, Blanchard S, Letexier M, Saraiva JP, Sahel JA, Audo I, Zeitz C (2018) A novel nonsense variant in REEP6 is involved in a sporadic rod-cone dystrophy case. Clin Genet 93(3):707–711. https://doi.org/10.1111/cge.13171

    Article  CAS  PubMed  Google Scholar 

  9. Hao H, Veleri S, Sun B, Kim DS, Keeley PW, Kim JW, Yang HJ, Yadav SP, Manjunath SH, Sood R, Liu P, Reese BE, Swaroop A (2014) Regulation of a novel isoform of Receptor Expression Enhancing Protein REEP6 in rod photoreceptors by bZIP transcription factor NRL. Hum Mol Genet 23(16):4260–4271. https://doi.org/10.1093/hmg/ddu143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Keeley PW, Luna G, Fariss RN, Skyles KA, Madsen NR, Raven MA, Poche RA, Swindell EC, Jamrich M, Oh EC, Swaroop A, Fisher SK, Reese BE (2013) Development and plasticity of outer retinal circuitry following genetic removal of horizontal cells. J Neurosci 33(45):17847–17862. https://doi.org/10.1523/JNEUROSCI.1373-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bjork S, Hurt CM, Ho VK, Angelotti T (2013) REEPs are membrane shaping adapter proteins that modulate specific g protein-coupled receptor trafficking by affecting ER cargo capacity. PLoS ONE 8(10):e76366. https://doi.org/10.1371/journal.pone.0076366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, Bach M (2015) ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 130(1):1–12. https://doi.org/10.1007/s10633-014-9473-7

    Article  PubMed  Google Scholar 

  13. Wang Y, Lichter-Konecki U, Anyane-Yeboa K, Shaw JE, Lu JT, Ostlund C, Shin JY, Clark LN, Gundersen GG, Nagy PL, Worman HJ (2016) A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder. J Cell Sci 129(10):1975–1980. https://doi.org/10.1242/jcs.187302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  15. Krogh A, Larsson B, von Heijne G, Sonnhammer EL (2001) Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol 305(3):567–580. https://doi.org/10.1006/jmbi.2000.4315

    Article  CAS  Google Scholar 

  16. Webb B, Sali A (2016) Comparative protein structure modeling using MODELLER. Curr Protoc Bioinform 54:561–5637. https://doi.org/10.1002/cpbi.3

    Article  Google Scholar 

  17. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22(22):4673–4680

    Article  CAS  Google Scholar 

  18. Agrawal SA, Burgoyne T, Eblimit A, Bellingham J, Parfitt DA, Lane A, Nichols R, Asomugha C, Hayes MJ, Munro PM, Xu M, Wang K, Futter CE, Li Y, Chen R, Cheetham ME (2017) REEP6 deficiency leads to retinal degeneration through disruption of ER homeostasis and protein trafficking. Hum Mol Genet 26(14):2667–2677. https://doi.org/10.1093/hmg/ddx149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vujosevic S, Bini S, Torresin T, Berton M, Midena G, Parrozzani R, Martini F, Pucci P, Daniele AR, Cavarzeran F, Midena E (2017) hyperreflective retinal spots in normal and diabetic eyes: B-scan and en face spectral domain optical coherence tomography evaluation. Retina 37(6):1092–1103. https://doi.org/10.1097/IAE.0000000000001304

    Article  PubMed  Google Scholar 

  20. Zhang L, Cui X, Jauregui R, Park KS, Justus S, Tsai YT, Duong JK, Hsu CW, Wu WH, Xu CL, Lin CS, Tsang SH (2018) Genetic rescue reverses microglial activation in preclinical models of retinitis pigmentosa. Mol Ther 26(8):1953–1964. https://doi.org/10.1016/j.ymthe.2018.06.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bonfiglio V, Reibaldi M, Pizzo A, Russo A, Macchi I, Faro G, Avitabile T, Longo A (2018) Dexamethasone for unresponsive diabetic macular oedema: optical coherence tomography biomarkers. Acta Ophthalmol. https://doi.org/10.1111/aos.13935

    Article  PubMed  Google Scholar 

  22. Uji A, Murakami T, Nishijima K, Akagi T, Horii T, Arakawa N, Muraoka Y, Ellabban AA, Yoshimura N (2012) Association between hyperreflective foci in the outer retina, status of photoreceptor layer, and visual acuity in diabetic macular edema. Am J Ophthalmol 153(4):710–717. https://doi.org/10.1016/j.ajo.2011.08.041

    Article  PubMed  Google Scholar 

  23. Tao LW, Wu Z, Guymer RH, Luu CD (2016) Ellipsoid zone on optical coherence tomography: a review. Clin Exp Ophthalmol 44(5):422–430. https://doi.org/10.1111/ceo.12685

    Article  PubMed  Google Scholar 

Download references

Funding

YCL is supported by the China Scholarship Council (No. 201806320164). SHT and the Jonas Children’s Vision Care is supported by the National Institute of Health 5P30CA013696, U01EY030580, R24EY027285, 5P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437, the Schneeweiss Stem Cell Fund, New York State [SDHDOH01-C32590GG-3450000], the Foundation Fighting Blindness New York Regional Research Center Grant [C-NY05-0705-0312], Nancy & Kobi Karp, the Crowley Family Funds, The Rosenbaum Family Foundation, Alcon Research Institute, the Gebroe Family Foundation, the Research to Prevent Blindness (RPB) Physician-Scientist Award, unrestricted funds from RPB, New York, NY, USA. JRS is supported by a NIH Grant [R01EY024091]. VBM is supported by NIH Grants [R01EY026682, R01EY024665, R01EY025225, R01EY024698, R21AG050437, and P30EY026877], and Research to Prevent Blindness (RPB), New York, NY. GV is supported by NIH Grants [F30EYE027986 and T32GM007337].

Author information

Authors and Affiliations

  1. Jonas Children’s Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Departments of Ophthalmology, Pathology and Cell Biology, Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Yuchen Lin, Christine L. Xu & Stephen H. Tsang

  2. Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China

    Yuchen Lin

  3. Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA

    Christine L. Xu, Mark P. Breazzano, Janet R. Sparrow & Stephen H. Tsang

  4. Omics Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA

    Gabriel Velez, Jing Yang & Vinit B. Mahajan

  5. Medical Scientist Training Program, University of Iowa, Iowa City, IA, USA

    Gabriel Velez

  6. Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Vinit B. Mahajan

  7. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA

    Akemi J. Tanaka & Janet R. Sparrow

  8. Department of Ophthalmology, New York University School of Medicine, New York, NY, USA

    Mark P. Breazzano

Authors
  1. Yuchen Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine L. Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gabriel Velez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akemi J. Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark P. Breazzano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vinit B. Mahajan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Janet R. Sparrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephen H. Tsang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen H. Tsang.

Ethics declarations

Conflict of interest

There are no conflicts of interest to disclose for any author.

Ethics approval and consent to participate

All study procedures were defined, and patient consent was obtained as outlined by the protocol #AAAB6560 approved by the Institutional Review Board at Columbia University Medical Center. The study adhered to the tenets of the Declaration of Helsinki.

Informed consent

Informed consent was obtained from the patient.

Statement of human rights

This study was approved by the Institutional Review Board of Columbia University Medical Center and adhered to the tenets of the Declaration of Helsinki.

Statement on the welfare of animals

This article does not contain any studies with animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, Y., Xu, C.L., Velez, G. et al. Novel REEP6 gene mutation associated with autosomal recessive retinitis pigmentosa. Doc Ophthalmol 140, 67–75 (2020). https://doi.org/10.1007/s10633-019-09719-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10633-019-09719-1

Keywords

Search

Navigation