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

Author:

Scelsi Hailee F.1ORCID,Hill Kamisha R.1ORCID,Barlow Brett M.1ORCID,Martin Mackenzie D.1ORCID,Lieberman Raquel L.1ORCID

Affiliation:

1. School of Chemistry & Biochemistry, Georgia Institute of Technology , 901 Atlantic Dr. NW, Atlanta, GA 30332-0400 , USA

Abstract

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 prevalent population-based variants using a suite of cellular and biophysical assays, and identified two variants with features of aggregation-prone familial disease variants. Next, we considered all available biochemical and clinical data to demonstrate that pathogenic and benign variants can be differentiated statistically based on a single metric: the thermal stability of OLF. Our results motivate genotyping MYOC in patients for clinical monitoring of this widespread, painless and irreversible ocular disease.

Funder

National Eye Institute

Georgia Institute of Technology

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

Reference64 articles.

1. A method and server for predicting damaging missense mutations;Adzhubei;Nat. Methods,2010

2. Towards automated crystallographic structure refinement with phenix.refine;Afonine;Acta Crystallogr. D,2012

3. Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma;Allingham;Invest. Ophthalmol. Vis. Sci.,1998

4. Epidemiology of Glaucoma: The Past, Present, and Predictions for the Future;Allison;Cureus,2020

5. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A);Alward;N. Engl. J. Med.,1998

Cited by 4 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller;Nature Communications;2024-01-02

2. Myocilin;Reference Module in Neuroscience and Biobehavioral Psychology;2024

3. Understanding the complex genetics and molecular mechanisms underlying glaucoma;Molecular Aspects of Medicine;2023-12

4. Myocilin misfolding and glaucoma: A 20-year update;Progress in Retinal and Eye Research;2023-07

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3