Journal
HUMAN MUTATION
Volume 42, Issue 8, Pages 903-946Publisher
WILEY-HINDAWI
DOI: 10.1002/humu.24238
Keywords
autosomal dominant; endoplasmic reticulum; glaucoma; gnomAD; Mendelian inheritance; misfolding; mutation; myocilin; pathogenesis; variant
Categories
Funding
- National Eye Institute [R01EY021205, T32EY007092]
Ask authors/readers for more resources
Rare variants of the olfactomedin domain of myocilin are considered to cause inherited glaucoma, with uncertainty surrounding the pathogenicity of many of these variants despite integration of various data types. The combination of metrics from different disciplines may help in resolving outstanding complexities and developing precision medicine therapeutics for this prevalent ocular disease.
Rare variants of the olfactomedin domain of myocilin are considered causative for inherited, early-onset open-angle glaucoma, with a misfolding toxic gain-of-function pathogenic mechanism detailed by 20 years of laboratory research. Myocilin variants are documented in the scientific literature and identified through large-scale genetic sequencing projects such as those curated in the Genome Aggregation Database (gnomAD). In the absence of key clinical and laboratory information, however, the pathogenicity of any given variant is not clear, because glaucoma is a heterogeneous and prevalent age-onset disease, and common variants are likely benign. In this review, we reevaluate the likelihood of pathogenicity for the similar to 100 nonsynonymous missense, insertion-deletion, and premature termination of myocilin olfactomedin variants documented in the literature. We integrate available clinical, laboratory cellular, biochemical and biophysical data, the olfactomedin domain structure, and population genetics data from gnomAD. Of the variants inspected, similar to 50% can be binned based on a preponderance of data, leaving many of uncertain pathogenicity that motivate additional studies. Ultimately, the approach of combining metrics from different disciplines will likely resolve outstanding complexities regarding the role of this misfolding-prone protein within the context of a multifactorial and prevalent ocular disease, and pave the way for new precision medicine therapeutics.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available