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Dopachrome tautomerase variants in patients with oculocutaneous albinism

Perrine Pennamen, Angèle Tingaud-Sequeira, Iveta Gazova, Margaret Keighren, Lisa McKie, Sandrine Marlin, Souad Gherbi Halem, Josseline Kaplan, Cédric Delevoye, Didier Lacombe, Claudio Plaisant, Vincent Michaud, Eulalie Lasseaux, Sophie Javerzat, View ORCID ProfileIan Jackson, Benoit Arveiler
doi: https://doi.org/10.1101/2020.06.26.171223
Perrine Pennamen
1Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France
2Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France
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Angèle Tingaud-Sequeira
1Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France
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Iveta Gazova
3MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK
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Margaret Keighren
3MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK
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Lisa McKie
3MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK
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Sandrine Marlin
4Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, Paris Descartes, Sorbonne Paris Cité University, Paris, France
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Souad Gherbi Halem
4Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, Paris Descartes, Sorbonne Paris Cité University, Paris, France
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Josseline Kaplan
5Laboratory of Genetics in Ophthalmology, Imagine Institute, Paris Descartes, Sorbonne Paris Cité University, Paris, France
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Cédric Delevoye
6Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, 75005 Paris, France
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Didier Lacombe
1Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France
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Claudio Plaisant
2Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France
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Vincent Michaud
2Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France
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Eulalie Lasseaux
2Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France
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Sophie Javerzat
1Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France
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Ian Jackson
3MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK
7Roslin Institute, University of Edinburgh, Edinburgh, UK
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  • ORCID record for Ian Jackson
Benoit Arveiler
1Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France
2Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France
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  • For correspondence: benoit.arveiler@chu-bordeaux.fr
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ABSTRACT

Purpose Albinism is a clinically and genetically heterogeneous condition. Despite analysis of the nineteen 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 mutations carried by the patients, along with one loss-of-function indel mutation. When bred to homozygosity the three mutations revealed hypopigmentation of the coat, milder for Cys40Ser compared to 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 melanocytes and RPE cells.

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

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflict of Interest Notification The authors declare no conflict of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 27, 2020.
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Dopachrome tautomerase variants in patients with oculocutaneous albinism
Perrine Pennamen, Angèle Tingaud-Sequeira, Iveta Gazova, Margaret Keighren, Lisa McKie, Sandrine Marlin, Souad Gherbi Halem, Josseline Kaplan, Cédric Delevoye, Didier Lacombe, Claudio Plaisant, Vincent Michaud, Eulalie Lasseaux, Sophie Javerzat, Ian Jackson, Benoit Arveiler
bioRxiv 2020.06.26.171223; doi: https://doi.org/10.1101/2020.06.26.171223
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Dopachrome tautomerase variants in patients with oculocutaneous albinism
Perrine Pennamen, Angèle Tingaud-Sequeira, Iveta Gazova, Margaret Keighren, Lisa McKie, Sandrine Marlin, Souad Gherbi Halem, Josseline Kaplan, Cédric Delevoye, Didier Lacombe, Claudio Plaisant, Vincent Michaud, Eulalie Lasseaux, Sophie Javerzat, Ian Jackson, Benoit Arveiler
bioRxiv 2020.06.26.171223; doi: https://doi.org/10.1101/2020.06.26.171223

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