Advertisement

Novel biallelic loss-of-function KCNV2 variants in cone dystrophy with supernormal rod responses

  • Tomoko Kutsuma
  • Satoshi Katagiri
  • Takaaki HayashiEmail author
  • Kazutoshi Yoshitake
  • Daisuke Iejima
  • Tamaki Gekka
  • Kenichi Kohzaki
  • Kei Mizobuchi
  • Yukari Baba
  • Ryo Terauchi
  • Tomokazu Matsuura
  • Shinji Ueno
  • Takeshi Iwata
  • Tadashi Nakano
Clinical Case Report

Abstract

Purpose

To report clinical and genetic features including long-term full-field electroretinography (FF-ERG) findings of a patient with cone dystrophy with supernormal rod responses (CDSRR).

Methods

Ophthalmological medical records including FF-ERG were retrospectively reviewed. Genetic analysis using whole-exome sequencing (WES) was performed. Identified KCNV2 variants were confirmed by Sanger sequencing.

Results

A 30-year-old female patient was referred to our hospital for assessment of decreased vision from childhood. Funduscopy showed macular atrophy in both eyes. FF-ERG showed decreased amplitudes and delayed peak time of b-waves for dark-adapted (DA) 0.01 ERG, increased b/a-wave ratio with a slightly diminished a-wave for DA 3.0 and DA 25.7 ERG, residual a-waves and almost extinguished b-waves for light-adapted (LA) 3.0 ERG, and extremely diminished amplitudes in LA 30-Hz flicker responses. At 45 years of age, funduscopy showed progressive macular atrophy, whereas the responses for her FF-ERG remained unchanged compared to those observed at 30 years of age. WES identified the compound heterozygous KCNV2 variants (p.W67X and p.D174GfsX198) in the patient. These variants have previously been unreported as pathogenic variants. Each parent had one of the variants. Subsequently, the patient was finally diagnosed with CDSRR with the novel compound heterozygous KCNV2 variants.

Conclusions

Biallelic loss-of-function KCNV2 variants (p.W67X and p.D174GfsX198) were identified as the cause of CDSRR. Long-term FF-ERG findings demonstrated there were no ERG changes during 15 years of observation, indicating that there was no evidence of progressive peripheral retinal dysfunction, in spite of worsening macular atrophy.

Keywords

KCNV2 Japanese Next-generation sequencing Cone dystrophy with supernormal rod response 

Notes

Acknowledgements

This work was supported by grants from the Practical Research Project for Rare/Intractable Diseases (17ek0109282h0001 for TI) from the Japan Agency for Medical Research and Development (AMED), and the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (17K11434 and 17K11441 for TH).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest regarding this paper.

Statement of human rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Statement on the welfare of animals

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

Informed consent

Informed consent was obtained from all participants included in the study.

Supplementary material

10633_2019_9679_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 17 kb)

References

  1. 1.
    Gouras P, Eggers HM, MacKay CJ (1983) Cone dystrophy, nyctalopia, and supernormal rod responses. A new retinal degeneration. Arch Ophthalmol 101:718–724CrossRefGoogle Scholar
  2. 2.
    Michaelides M, Johnson S, Simunovic MP, Bradshaw K, Holder G, Mollon JD, Moore AT, Hunt DM (2005) Blue cone monochromatism: a phenotype and genotype assessment with evidence of progressive loss of cone function in older individuals. Eye (Lond) 19:2–10CrossRefGoogle Scholar
  3. 3.
    Robson AG, Webster AR, Michaelides M, Downes SM, Cowing JA, Hunt DM, Moore AT, Holder GE (2010) “Cone dystrophy with supernormal rod electroretinogram”: a comprehensive genotype/phenotype study including fundus autofluorescence and extensive electrophysiology. Retina 30:51–62CrossRefGoogle Scholar
  4. 4.
    Vincent A, Robson AG, Holder GE (2013) Pathognomonic (diagnostic) ERGs. A review and update. Retina 33:5–12CrossRefGoogle Scholar
  5. 5.
    Gayet-Primo J, Yaeger DB, Khanjian RA, Puthussery T (2018) Heteromeric KV2/KV8.2 channels mediate delayed rectifier potassium currents in primate photoreceptors. J Neurosci 38:3414–3427CrossRefGoogle Scholar
  6. 6.
    Wu H, Cowing JA, Michaelides M, Wilkie SE, Jeffery G, Jenkins SA, Mester V, Bird AC, Robson AG, Holder GE, Moore AT, Hunt DM, Webster AR (2006) Mutations in the gene KCNV2 encoding a voltage-gated potassium channel subunit cause “cone dystrophy with supernormal rod electroretinogram” in humans. Am J Hum Genet 79:574–579CrossRefGoogle Scholar
  7. 7.
    Ottschytsch N, Raes A, Van Hoorick D, Snyders DJ (2002) Obligatory heterotetramerization of three previously uncharacterized Kv channel alpha-subunits identified in the human genome. Proc Natl Acad Sci USA 99:7986–7991CrossRefGoogle Scholar
  8. 8.
    Czirjak G, Toth ZE, Enyedi P (2007) Characterization of the heteromeric potassium channel formed by kv2.1 and the retinal subunit kv8.2 in Xenopus oocytes. J Neurophysiol 98:1213–1222CrossRefGoogle Scholar
  9. 9.
    Holter P, Kunst S, Wolloscheck T, Kelleher DK, Sticht C, Wolfrum U, Spessert R (2012) The retinal clock drives the expression of Kcnv2, a channel essential for visual function and cone survival. Invest Ophthalmol Vis Sci 53:6947–6954CrossRefGoogle Scholar
  10. 10.
    Wissinger B, Schaich S, Baumann B, Bonin M, Jagle H, Friedburg C, Varsanyi B, Hoyng CB, Dollfus H, Heckenlively JR, Rosenberg T, Rudolph G, Kellner U, Salati R, Plomp A, De Baere E, Andrassi-Darida M, Sauer A, Wolf C, Zobor D, Bernd A, Leroy BP, Enyedi P, Cremers FP, Lorenz B, Zrenner E, Kohl S (2011) Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response. Hum Mutat 32:1398–1406CrossRefGoogle Scholar
  11. 11.
    Wissinger B, Dangel S, Jagle H, Hansen L, Baumann B, Rudolph G, Wolf C, Bonin M, Koeppen K, Ladewig T, Kohl S, Zrenner E, Rosenberg T (2008) Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2. Invest Ophthalmol Vis Sci 49:751–757CrossRefGoogle Scholar
  12. 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 130:1–12CrossRefGoogle Scholar
  13. 13.
    Takeuchi T, Hayashi T, Bedell M, Zhang K, Yamada H, Tsuneoka H (2010) A novel haplotype with the R345 W mutation in the EFEMP1 gene associated with autosomal dominant drusen in a Japanese family. Invest Ophthalmol Vis Sci 51:1643–1650CrossRefGoogle Scholar
  14. 14.
    Katagiri S, Yoshitake K, Akahori M, Hayashi T, Furuno M, Nishino J, Ikeo K, Tsuneoka H, Iwata T (2013) Whole-exome sequencing identifies a novel ALMS1 mutation (p. Q2051X) in two Japanese brothers with Alstrom syndrome. Mol Vis 19:2393–2406Google Scholar
  15. 15.
    Katagiri S, Akahori M, Sergeev Y, Yoshitake K, Ikeo K, Furuno M, Hayashi T, Kondo M, Ueno S, Tsunoda K, Shinoda K, Kuniyoshi K, Tsurusaki Y, Matsumoto N, Tsuneoka H, Iwata T (2014) Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa. PLoS ONE 9:e108721CrossRefGoogle Scholar
  16. 16.
    Verriest G, Van Laethem J, Uvijls A (1982) A new assessment of the normal ranges of the Farnsworth–Munsell 100-hue test scores. Am J Ophthalmol 93:635–642CrossRefGoogle Scholar
  17. 17.
    Vincent A, Wright T, Garcia-Sanchez Y, Kisilak M, Campbell M, Westall C, Heon E (2013) Phenotypic characteristics including in vivo cone photoreceptor mosaic in KCNV2-related “cone dystrophy with supernormal rod electroretinogram”. Invest Ophthalmol Vis Sci 54:898–908CrossRefGoogle Scholar
  18. 18.
    Nakamura N, Tsunoda K, Fujinami K, Shinoda K, Tomita K, Hatase T, Usui T, Akahori M, Iwata T, Miyake Y (2013) Long-term observation over ten years of four cases of cone dystrophy with supernormal rod electroretinogram. Nippon Ganka Gakkai Zasshi 117:629–640Google Scholar
  19. 19.
    Ben Salah S, Kamei S, Senechal A, Lopez S, Bazalgette C, Bazalgette C, Eliaou CM, Zanlonghi X, Hamel CP (2008) Novel KCNV2 mutations in cone dystrophy with supernormal rod electroretinogram. Am J Ophthalmol 145:1099–1106CrossRefGoogle Scholar
  20. 20.
    Sergouniotis PI, Holder GE, Robson AG, Michaelides M, Webster AR, Moore AT (2012) High-resolution optical coherence tomography imaging in KCNV2 retinopathy. Br J Ophthalmol 96:213–217CrossRefGoogle Scholar
  21. 21.
    Michaelides M, Holder GE, Webster AR, Hunt DM, Bird AC, Fitzke FW, Mollon JD, Moore AT (2005) A detailed phenotypic study of “cone dystrophy with supernormal rod ERG”. Br J Ophthalmol 89:332–339CrossRefGoogle Scholar
  22. 22.
    Xu D, Su D, Nusinowitz S, Sarraf D (2017) Central ellipsoid loss associated with cone dystrophy and KCNV2 mutation. Retin Cases Brief Rep 12:S59–S62CrossRefGoogle Scholar
  23. 23.
    Sieving PA, Murayama K, Naarendorp F (1994) Push-pull model of the primate photopic electroretinogram: a role for hyperpolarizing neurons in shaping the b-wave. Vis Neurosci 11:519–532CrossRefGoogle Scholar
  24. 24.
    Zobor D, Kohl S, Wissinger B, Zrenner E, Jagle H (2012) Rod and cone function in patients with KCNV2 retinopathy. PLoS ONE 7:e46762CrossRefGoogle Scholar
  25. 25.
    Fujinami K, Tsunoda K, Nakamura N, Kato Y, Noda T, Shinoda K, Tomita K, Hatase T, Usui T, Akahori M, Itabashi T, Iwata T, Ozawa Y, Tsubota K, Miyake Y (2013) Molecular characteristics of four Japanese cases with KCNV2 retinopathy: report of novel disease-causing variants. Mol Vis 19:1580–1590Google Scholar
  26. 26.
    Oishi M, Oishi A, Gotoh N, Ogino K, Higasa K, Iida K, Makiyama Y, Morooka S, Matsuda F, Yoshimura N (2016) Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies. Mol Vis 22:150–160Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of OphthalmologyThe Jikei University School of MedicineTokyoJapan
  2. 2.Department of Ophthalmology, Katsushika Medical CenterThe Jikei University School of MedicineTokyoJapan
  3. 3.National Institute of Sensory OrgansNational Hospital Organization Tokyo Medical CenterTokyoJapan
  4. 4.Department of Laboratory MedicineThe Jikei University School of MedicineTokyoJapan
  5. 5.Department of OphthalmologyNagoya University Graduate School of MedicineNagoyaJapan

Personalised recommendations