Identification and characterization of two novel noncoding tyrosinase (TYR) gene variants leading to oculocutaneous albinism type 1

Oculocutaneous albinism type 1 (OCA1), resulting from pathogenic variants in the tyrosinase (TYR) gene, refers to a group of phenotypically heterogeneous autosomal recessive disorders characterized by a partial or a complete absence of pigment in the skin/hair and is also associated with common developmental eye defects. In this study, we identified two novel compound heterozygous TYR variants from a Chinese hypopigmentary patient by whole-exome sequencing. Specif-ically, the two variants were c.-89T > G, located at the core of the initiator E-box (Inr E-box) of the TYR promoter, and p.S16Y (c.47C > A), located within the signal sequence. We performed both in silico analysis and experimental validation and verified these mutations as OCA1 variants that caused either impaired or complete loss of function of TYR. Mecha-nistically, the Inr E-box variant dampened TYR binding to microphthalmia-associated transcription factor, a master transcriptional regulator of the melanocyte development, whereas the S16Y variant contributed to endoplasmic reticu-lum retention, a common and principal cause of impaired TYR activity. Interestingly, we found that the Inr E-box variant creates novel protospacer adjacent motif sites, recognized by nucleases SpCas9 and SaCas9-KKH, respectively, without compromising the functional TYR coding sequence. We further used allele-specific genomic editing by CRISPR acti-vation to specifically target the variant promoter and success-fully activated its downstream gene expression, which could lead to potential therapeutic benefits. In conclusion, this study expands the spectrum of TYR variants, especially those within the promoter and noncoding regions, which can facilitate ge-netic counseling and clinical diagnosis of OCA1.

Automated summary

This study identified two novel compound heterozygous TYR variants in a Chinese patient with hypopigmentation. The variants were found to cause impaired or complete loss of function of TYR, and one variant showed potential therapeutic benefits through gene editing. This study expands the understanding of TYR variants in OCA1 and can facilitate genetic counseling and clinical diagnosis.