Dopachrome tautomerase variants in patients with oculocutaneous albinism

Abstract

Purpose

Albinism is a clinically and genetically heterogeneous condition. Despite analysis of the 20 known genes, ~30% patients remain unsolved. We aimed to identify new genes involved in albinism.

Methods

We sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients.

Results

We identified variants in the Dopachrome tautomerase (DCT) gene in two patients. One was compound heterozygous for a 14-bp deletion in exon 9 and c.118T>A p.(Cys40Ser). The second was homozygous for c.183C>G p.(Cys61Trp). Both patients had mild hair and skin hypopigmentation, and classical ocular features. CRISPR-Cas9 was used in C57BL/6J mice to create mutations identical to the missense variants carried by the patients, along with one loss-of-function indel. When bred to homozygosity the three mutations revealed hypopigmentation of the coat, milder for Cys40Ser compared with Cys61Trp or the frameshift mutation. Histological analysis identified significant hypopigmentation of the retinal pigmented epithelium (RPE) indicating that defective RPE melanogenesis could be associated with eye and vision defects. DCT loss of function in zebrafish embryos elicited hypopigmentation both in melanophores and RPE cells.

Conclusion

DCT is the gene for a new type of oculocutaneous albinism that we propose to name OCA8.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Phenotype and genotype of patients 1 and 2.
Fig. 2: Amino acid sequences alignment for the human tyrosinase family and DCT sequences of other species.
Fig. 3: Patient variants have a visible effect on pigmentation of the coat and eyes in mice.
Fig. 4: dct is required for skin melanophores and retinal pigment epithelium (RPE) development preservation in zebrafish D. rerio.

References

  1. 1.

    Grønskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007;2:43–51.

    Article  Google Scholar 

  2. 2.

    Montoliu L, Grønskov K, Wei AH, et al. Increasing the complexity: new genes and new types of albinism. Pigment Cell Melanoma Res. 2014;27:11–18.

    CAS  Article  Google Scholar 

  3. 3.

    Kruijt CC, de Wit GC, Bergen AA, Florijn RJ, Schalij-Delfos NE, van Genderen MM. The phenotypic spectrum of albinism. Ophthalmology. 2018;125:1953–1960.

    Article  Google Scholar 

  4. 4.

    Poulter JA, Al-Araimi M, Conte I, et al. Recessive mutations in SLC38a8 cause foveal hypoplasia and optic nerve misrouting without albinism. Am J Hum Genet. 2013;93:1143–1150.

    CAS  Article  Google Scholar 

  5. 5.

    Lasseaux E, Plaisant C, Michaud V, et al. Molecular characterization of a series of 990 index patients with albinism. Pigment Cell Melanoma Res. 2018;31:466–474.

    CAS  Article  Google Scholar 

  6. 6.

    Pennamen P, Le L, Tingaud-Sequeira A, et al. BLOC1S5 pathogenic variants cause a new type of Hermansky–Pudlak syndrome. Genet Med. 2020. https://doi.org/10.1038/s41436-020-0867-5 [Epub ahead of print].

  7. 7.

    Gargiulo A, Testa F, Rossi S, et al. Molecular and clinical characterization of albinism in a large cohort of Italian patients. Invest Ophthalmol Vis Sci. 2011;52:1281–1289.

    CAS  Article  Google Scholar 

  8. 8.

    Hutton SM, Spritz RA. Comprehensive analysis of oculocutaneous albinism among non-Hispanic caucasians shows that OCA1 Is the most prevalent OCA type. J Invest Dermatol. 2008;128:2442–2450.

    CAS  Article  Google Scholar 

  9. 9.

    Zhong Z, Gu L, Zheng X, et al. Comprehensive analysis of spectral distribution of a large cohort of Chinese patients with non-syndromic oculocutaneous albinism facilitates genetic diagnosis. Pigment Cell Melanoma Res. 2019;32:672–686.

    CAS  Article  Google Scholar 

  10. 10.

    Lai X, Wichers HJ, Soler-Lopez M, Dijkstra BW. Structure and function of human tyrosinase and Tyrosinase-related proteins. Chemistry. 2018;24:47–55.

    CAS  Article  Google Scholar 

  11. 11.

    Murisier F, Beermann F. Genetics of pigment cells: lessons from the tyrosinase gene family. Histol Histopathol. 2006;21:567–578.

    CAS  PubMed  Google Scholar 

  12. 12.

    Budd PS, Jackson IJ. Structure of the mouse tyrosinase-related protein-2/dopachrome tautomerase (Tyrp2/Dct) gene and sequence of two novel slaty alleles. Genomics. 1995;29:35–43.

    CAS  Article  Google Scholar 

  13. 13.

    Cross SH, Mckie L, Keighren M, et al. Missense mutations in the human nanophthalmos gene TMEM98 cause retinal defects in the mouse. Invest Ophthalmol Vis Sci. 2019;60:2875–2887.

    CAS  Article  Google Scholar 

  14. 14.

    Mengel-From J, Wong TH, Morling N, Rees JL, Jackson IJ. Genetic determinants of hair and eye colours in the Scottish and Danish populations. BMC Genet. 2009;10:1–13.

    Article  Google Scholar 

  15. 15.

    Manga P, Sheyn D, Yang F, Sarangarajan R, Boissy RE. A role for tyrosinase-related protein 1 in 4-tert-butylphenol-induced toxicity in melanocytes: Implications for vitiligo. Am J Pathol. 2006;169:1652–1662.

    CAS  Article  Google Scholar 

  16. 16.

    Thomas MG, Kumar A, Mohammad S, et al. Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography: a predictor of visual acuity? Ophthalmology. 2011;118:1653–1660.

    Article  Google Scholar 

  17. 17.

    Richards S, Aziz N, Bale S, et al. 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. 2015;17:405–424.

    Article  Google Scholar 

  18. 18.

    Guyonneau L, Murisier F, Rossier A, Moulin A, Beermann F. Melanocytes and pigmentation are affected in dopachrome tautomerase knockout mice. Mol Cell Biol. 2004;24:3396–3403.

    CAS  Article  Google Scholar 

  19. 19.

    Jackson IJ, Chambers DM, Tsukamoto K, et al. A second tyrosinase-related protein, TRP-2, maps to and is mutated at the mouse slaty locus. EMBO J. 1992;11:527–535.

    CAS  Article  Google Scholar 

  20. 20.

    Bedell VM, Westcot SE, Ekker SC. Lessons from morpholino-based screening in zebrafish. Brief Funct Genomics. 2011;10:181–188.

    CAS  Article  Google Scholar 

  21. 21.

    Rooryck C, Roudaut C, Robine E, Müsebeck J, Arveiler B. Oculocutaneous albinism with TYRP1 gene mutations in a Caucasian patient. Pigment Cell Res. 2006;19:239–242.

    CAS  Article  Google Scholar 

  22. 22.

    Jaworek TJ, Kausar T, Bell SM, et al. Molecular genetic studies and delineation of the oculocutaneous albinism phenotype in the Pakistani population. Orphanet J Rare Dis. 2012;7:44–63.

    Article  Google Scholar 

  23. 23.

    King RA, Mentink MM, Oetting WS. Non-random distribution of missense mutations within the human tyrosinase gene in type I (tyrosinase-related) oculocutaneous albinism. Mol Biol Med. 1991;8:19–29.

    CAS  PubMed  Google Scholar 

  24. 24.

    Urtatiz O, Sanabria D, Lattig MC. Oculocutaneous albinism (OCA) in Colombia: first molecular screening of the TYR and OCA2 genes in South America. J Dermatol Sci. 2014;76:260–262.

    CAS  Article  Google Scholar 

  25. 25.

    Shahzad M, Yousaf S, Waryah YM, et al. Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population. Sci Rep. 2017;7:44185. https://doi.org/10.1038/srep44185.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Yamada M, Sakai K, Hayashi M, et al. Oculocutaneous albinism type 3: a Japanese girl with novel mutations in TYRP1 gene. J Dermatol Sci. 2011;64:217–222.

    CAS  Article  Google Scholar 

  27. 27.

    Yokoyama T, Silversides DW, Waymire KG, Kwon BS, Takeuchi T, Overbeek PA. Conserved cysteine to serine mutation in tyrosinase is responsible for the classical albino mutation in laboratory mice. Nucleic Acids Res. 1990;18:7293–7298.

    CAS  Article  Google Scholar 

  28. 28.

    Jackson IJ, Bennett DC. Identification of the albino mutation of mouse tyrosinase by analysis of an in vitro revertant. Proc Natl Acad Sci U S A. 1990;87:7010–7014.

    CAS  Article  Google Scholar 

  29. 29.

    Zdarsky E, Favor J, Jackson IJ. The molecular basis of brown, an old mouse mutation, and of an induced revertant to wild type. Genetics. 1990;126:443–449.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Raymond SM, Jackson IJ. The retinal pigmented epithelium is required for development and maintenance of the mouse neural retina. Curr Biol. 1995;5:1286–1295.

    CAS  Article  Google Scholar 

  31. 31.

    Mason C, Guillery R. Conversations with Ray Guillery on albinism: linking Siamese cat visual pathway connectivity to mouse retinal development. Eur J Neurosci. 2019;49:913–927.

    Article  Google Scholar 

  32. 32.

    Prieur DS, Rebsam A. Retinal axon guidance at the midline: chiasmatic misrouting and consequences. Dev Neurobiol. 2017;77:844–860.

    CAS  Article  Google Scholar 

  33. 33.

    Roffler-Tarlov S, Liu JH, Naumova EN, Bernal-Ayala MM, Mason CA. L-Dopa and the albino riddle: content of L-Dopa in the developing retina of pigmented and albino mice. PLoS One. 2013;8:e57184.

    CAS  Article  Google Scholar 

  34. 34.

    Lavado A, Jeffery G, Tovar V, De La Villa P, Montoliu L. Ectopic expression of tyrosine hydroxylase in the pigmented epithelium rescues the retinal abnormalities and visual function common in albinos in the absence of melanin. J Neurochem. 2006;96:1201–1211.

    CAS  Article  Google Scholar 

  35. 35.

    Richardson R, Tracey-White D, Webster A, Moosajee M. The zebrafish eye-a paradigm for investigating human ocular genetics. Eye. 2017;31:68–86.

    CAS  Article  Google Scholar 

  36. 36.

    Logan DW, Burn SF, Jackson IJ. Regulation of pigmentation in zebrafish melanophores. Pigment Cell Res. 2006;19:206–213.

    CAS  Article  Google Scholar 

  37. 37.

    Braasch I, Liedtke D, Volff JN, Schartl M. Pigmentary function and evolution of tyrp1 gene duplicates in fish. Pigment Cell Melanoma Res. 2009;22:839–850.

    CAS  Article  Google Scholar 

  38. 38.

    Lamason RL, Mohideen MAPK, Mest JR, et al. Genetics: SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science. 2005;310:1782–1785.

    CAS  Article  Google Scholar 

  39. 39.

    Gross JM, Perkins BD, Amsterdam A, et al. Identification of Zebrafish insertional mutants with defects in visual system development and function. Genetics. 2005;170:245–261.

    CAS  Article  Google Scholar 

  40. 40.

    Arveiler B, Michaud V, Lasseaux E. Albinism: an underdiagnosed condition. J Invest Dermatol. 2020;140:1449–1451.

Download references

Acknowledgements

The authors are grateful to the French Albinism Association Genespoir for financial support and for timeless action in favor of patients with albinism. I.G., L.M., M.K., and I.J.J. were funded by the MRC University Unit award to the MRC Human Genetics Unit, grant number MC_UU_00007/4. The authors also thank the patients for participating in this study and Angus Reid for assisting with colorimetric measurements.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Benoit Arveiler PharmD, PhD.

Ethics declarations

Disclosure

The authors declare no conflicts of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pennamen, P., Tingaud-Sequeira, A., Gazova, I. et al. Dopachrome tautomerase variants in patients with oculocutaneous albinism. Genet Med (2020). https://doi.org/10.1038/s41436-020-00997-8

Download citation

Keywords

  • albinism
  • pigmentation
  • DCT
  • mouse
  • zebrafish.

Further reading

Search