PubMed ID: 40060664
Author(s): Hill KR, Scelsi HF, Youngblood HA, Faralli JA, Itakura T, Fini ME, Peters DM, Lieberman RL. Structural basis for anomalous cellular trafficking behavior of glaucoma-associated A427T mutant myocilin. bioRxiv [Preprint]. 2025 Feb 27:2025.02.26.640437. doi: 10.1101/2025.02.26.640437. PMID 40060664
Journal: Bio Rxiv : The Preprint Server For Biology, Feb 2025
UNLABELLED Familial mutations in myocilin cause vision loss in glaucoma due to misfolding and a toxic gain of function in a senescent cell type in the anterior eye. Here we characterize the cellular behavior and structure of the myocilin (myocilin A427T ) mutant, of uncertain pathogenicity. Our characterization of A427T demonstrates that even mutations that minimally perturb myocilin structure and stability can present challenges for protein quality control clearance pathways. Namely, when expressed in an inducible immortalized trabecular meshwork cell line, inhibition of the proteasome reroutes wild-type myocilin, but not myocilin A427T , from endoplasmic reticulum associated degradation to lysosomal degradation. Yet, the crystal structure of the A427T myocilin olfactomedin domain shows modest perturbations largely confined to the mutation site. The previously unappreciated range of mutant myocilin behavior correlating with variable stability and structure provides a rationale for why it is challenging to predict causal pathogenicity of a given myocilin mutation, even in the presence of clinical data for members of an affected family. Comprehending the continuum of mutant myocilin behavior in the laboratory supports emerging efforts to use genetics to assess glaucoma risk in the clinic. In addition, the study supports a therapeutic strategy aimed at enhancing autophagic clearance of mutant myocilin.
SIGNIFICANCE STATEMENT Rare familial mutations cause early onset glaucomaA427T is a case of uncertain pathogenicityA427T is structurally similar to wild-type but is not efficiently degraded.