The degradation of TYR variants derived from Chinese OCA families is mediated by the ERAD and ERLAD pathway.

Oculocutaneous albinism (OCA) is a genetically heterogeneous group of autosomal recessive disorders, which presents with decreased or absent pigmentation in the hair, skin, and eyes. OCA1, as a subtype of OCA, is caused by mutations in the tyrosinase gene (TYR). In this study, we performed in vitro functional analysis of eight TYR variants (one frameshift variant: c.929dupC (p.Arg311Lysfs*7); seven missense variants: c.896G>A (p.Arg299His), c.1234C>A (p.Pro412Thr), c.1169A>G (p.His390Arg), c.937C>A (p.Pro313Thr), c.636A>T (p.Arg212Ser), c.623 T>G (p.Leu208Arg), c.1325C>A (p.Ser442Tyr)) identified in Chinese OCA families. TYR plasmids were transfected into HEK 293 T cells to explore the effects of TYR variants on their processing, protein expression, activity, and degradation. The results showed that all eight variants caused TYR to be retained in the endoplasmic reticulum (ER), processing was blocked, and TYR activity almost disappeared; the frameshift variant caused the size of the TYR protein to be reduced by about 30KD, and the protein expression of the remaining seven missense variants was reduced; the ER-associated degradation (ERAD) pathway mediates the degradation of TYR variants that occur on the Tyrosinase copper-binding domain, while the degradation of TYR variants that are not located on that domain may be mediated by a new degradation pathway--ER-to-lysosome-associated degradation (ERLAD). In summary, TYR variants affected their protein processing and activity, and may also induce ER stress and trigger degradation through the ERLAD pathway in addition to the ERAD degradation pathway, providing new insights into the potential pathogenic mechanism for OCA1 caused by TYR variants.