Dopachrome tautomerase variants in patients with oculocutaneous albinism.
DCT
albinism
mouse
pigmentation
zebrafish.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
26
06
2020
accepted:
24
09
2020
revised:
24
09
2020
pubmed:
27
10
2020
medline:
4
6
2021
entrez:
26
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33100333
doi: 10.1038/s41436-020-00997-8
pii: S1098-3600(21)04940-6
doi:
Substances chimiques
Intramolecular Oxidoreductases
EC 5.3.-
dopachrome isomerase
EC 5.3.3.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
479-487Subventions
Organisme : Medical Research Council
ID : MC_UU_00007/4
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
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