1. Dopachrome tautomerase variants in patients with oculocutaneous albinism
- Author
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Vincent Michaud, Ian J. Jackson, Angèle Tingaud-Sequeira, Margaret A. Keighren, Didier Lacombe, Souad Gherbi Halem, Josseline Kaplan, Perrine Pennamen, Sandrine Marlin, Lisa McKie, Benoit Arveiler, Sophie Javerzat, Eulalie Lasseaux, Cédric Delevoye, Iveta Gazova, Claudio Plaisant, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], University of Edinburgh, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Admin, Oskar, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
- Subjects
0301 basic medicine ,Mouse ,Albinism ,030105 genetics & heredity ,Biology ,Compound heterozygosity ,Frameshift mutation ,Mice ,03 medical and health sciences ,Exon ,0302 clinical medicine ,medicine ,Animals ,Humans ,Missense mutation ,Genetics (clinical) ,Zebrafish ,030304 developmental biology ,Hypopigmentation ,Genetics ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Pigmentation ,DCT ,medicine.disease ,Oculocutaneous albinism ,3. Good health ,Intramolecular Oxidoreductases ,Mice, Inbred C57BL ,030104 developmental biology ,Albinism, Oculocutaneous ,030220 oncology & carcinogenesis ,Mutation ,medicine.symptom ,Dopachrome tautomerase ,INDEL Mutation ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
PurposeAlbinism 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.MethodsWe sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients.ResultsWe identified variants in theDopachrome 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.DCTloss of function in zebrafish embryos elicited hypopigmentation both in melanocytes and RPE cells.ConclusionsDCTis the gene for a new type of oculocutaneous albinism that we propose to name OCA8.
- Published
- 2021