Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France.
Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France.
Genet Med. 2021 Mar;23(3):479-487. doi: 10.1038/s41436-020-00997-8. Epub 2020 Oct 26.
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.
We sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients.
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.
DCT is the gene for a new type of oculocutaneous albinism that we propose to name OCA8.
白化病是一种临床表现和遗传异质性的疾病。尽管对 20 个已知基因进行了分析，但仍有约 30%的患者未得到明确诊断。我们旨在鉴定新的与白化病相关的基因。
我们对 230 名未明确诊断的白化病患者的一组已知或预测与黑色素生成相关的基因进行了测序分析。
我们在两名患者的 Dopachrome tautomerase（DCT）基因中发现了变异。一位患者是外显子 9 中 14 个碱基对缺失的复合杂合子，c.118T>A p.(Cys40Ser)。第二位患者是 c.183C>G p.(Cys61Trp)的纯合子。两名患者均有轻度毛发和皮肤色素减退，以及典型的眼部特征。CRISPR-Cas9 被用于 C57BL/6J 小鼠，以创建与患者携带的错义变异相同的突变，以及一个缺失功能的插入缺失。当纯合时，这三种突变导致毛色色素减退，Cys40Ser 比 Cys61Trp 或移码突变更轻。组织学分析发现视网膜色素上皮（RPE）明显色素减退，表明 RPE 黑色素生成缺陷可能与眼睛和视力缺陷有关。DCT 在斑马鱼胚胎中的功能丧失会引起黑素细胞和 RPE 细胞的色素减退。
DCT 是一种新的眼皮肤白化病的致病基因，我们建议将其命名为 OCA8。
