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Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data

2021; Wiley; Volume: 42; Issue: 8 Linguagem: Inglês

10.1002/humu.24238

1098-1004

Hailee F. Scelsi, Brett M. Barlow, Emily Saccuzzo, Raquel L. Lieberman,

Glycosylation and Glycoproteins Research

Human MutationVolume 42, Issue 8 p. 903-946 REVIEW Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data Hailee F. Scelsi, orcid.org/0000-0001-5033-8550 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USASearch for more papers by this authorBrett M. Barlow, orcid.org/0000-0002-5132-1520 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USASearch for more papers by this authorEmily G. Saccuzzo, orcid.org/0000-0001-7772-7740 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USASearch for more papers by this authorRaquel L. Lieberman, Corresponding Author Raquel.lieberman@chemistry.gatech.edu orcid.org/0000-0001-9345-3735 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USA Correspondence Raquel L. Lieberman, School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Dr. NW, Atlanta, GA 30332, USA. Email: Raquel.lieberman@chemistry.gatech.eduSearch for more papers by this author Hailee F. Scelsi, orcid.org/0000-0001-5033-8550 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USASearch for more papers by this authorBrett M. Barlow, orcid.org/0000-0002-5132-1520 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USASearch for more papers by this authorEmily G. Saccuzzo, orcid.org/0000-0001-7772-7740 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USASearch for more papers by this authorRaquel L. Lieberman, Corresponding Author Raquel.lieberman@chemistry.gatech.edu orcid.org/0000-0001-9345-3735 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USA Correspondence Raquel L. Lieberman, School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Dr. NW, Atlanta, GA 30332, USA. Email: Raquel.lieberman@chemistry.gatech.eduSearch for more papers by this author First published: 03 June 2021 https://doi.org/10.1002/humu.24238Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract 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 ~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, ~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. Open Research DATA AVAILABILITY STATEMENT Data sharing not applicable–no new data generated. Clinical data collected in Table S1. Supporting Information Filename Description humu24238-sup-0001-Supp_Table_S1.xlsx460.5 KB Supporting information. humu24238-sup-0002-Supp_Mat_2.docx353.2 KB Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume42, Issue8August 2021Pages 903-946 This article also appears in:Editor's Choice Articles RelatedInformation