Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability.

ABSTRACT: Accurate predictions of the pathogenicity of mutations associated with genetic diseases are key to the success of precision medicine. Inherited missense mutations in the myocilin (MYOC) gene, within its olfactomedin (OLF) domain, constitute the strongest genetic link to primary open-angle glaucoma via a toxic gain of function, and thus MYOC is an attractive precision-medicine target. However, not all mutations in MYOC cause glaucoma, and common variants are expected to be neutral polymorphisms. The Genome Aggregation Database (gnomAD) lists ∼100 missense variants documented within OLF, all of which are relatively rare (allele frequency <0.001%) and nearly all are of unknown pathogenicity. To distinguish disease-causing OLF variants from benign OLF variants, we first characterized the most

SUBMITTER: Scelsi HF 

PROVIDER: S-EPMC9844228 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature