PT  - JOURNAL ARTICLE
AU  - Perrine Pennamen
AU  - Angèle Tingaud-Sequeira
AU  - Iveta Gazova
AU  - Margaret Keighren
AU  - Lisa McKie
AU  - Sandrine Marlin
AU  - Souad Gherbi Halem
AU  - Josseline Kaplan
AU  - Cédric Delevoye
AU  - Didier Lacombe
AU  - Claudio Plaisant
AU  - Vincent Michaud
AU  - Eulalie Lasseaux
AU  - Sophie Javerzat
AU  - Ian Jackson
AU  - Benoit Arveiler
TI  - Dopachrome tautomerase variants in patients with oculocutaneous albinism
AID  - 10.1101/2020.06.26.171223
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.26.171223
4099  - http://biorxiv.org/content/early/2020/06/27/2020.06.26.171223.short
4100  - http://biorxiv.org/content/early/2020/06/27/2020.06.26.171223.full
AB  - 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 StatementThe authors have declared no competing interest.