Perrine Pennamen1,2, Angèle Tingaud-Sequeira1, Iveta Gazova3, Margaret Keighren3, Lisa McKie3, Sandrine Marlin4, Souad Gherbi Halem4, Josseline Kaplan5, Cédric Delevoye6, Didier Lacombe1, Claudio Plaisant2, Vincent Michaud2, Eulalie Lasseaux2, Sophie Javerzat1, Ian Jackson3,7, Benoit Arveiler8,9. 1. Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France. 2. Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France. 3. MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK. 4. Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, Paris Descartes, Sorbonne Paris Cité University, Paris, France. 5. Laboratory of Genetics in Ophthalmology, Imagine Institute, Paris Descartes, Sorbonne Paris Cité University, Paris, France. 6. Institut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, Paris, France. 7. Roslin Institute, University of Edinburgh, Edinburgh, UK. 8. Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France. benoit.arveiler@chu-bordeaux.fr. 9. Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France. benoit.arveiler@chu-bordeaux.fr.
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.
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.
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