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

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 v...

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Autores principales: Scelsi, Hailee F., Hill, Kamisha R., Barlow, Brett M., Martin, Mackenzie D., Lieberman, Raquel L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844228/
https://www.ncbi.nlm.nih.gov/pubmed/36579626
http://dx.doi.org/10.1242/dmm.049816
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author Scelsi, Hailee F.
Hill, Kamisha R.
Barlow, Brett M.
Martin, Mackenzie D.
Lieberman, Raquel L.
author_facet Scelsi, Hailee F.
Hill, Kamisha R.
Barlow, Brett M.
Martin, Mackenzie D.
Lieberman, Raquel L.
author_sort Scelsi, Hailee F.
collection PubMed
description 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.
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spelling pubmed-98442282023-01-18 Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability Scelsi, Hailee F. Hill, Kamisha R. Barlow, Brett M. Martin, Mackenzie D. Lieberman, Raquel L. Dis Model Mech Research Article 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. The Company of Biologists Ltd 2023-01-13 /pmc/articles/PMC9844228/ /pubmed/36579626 http://dx.doi.org/10.1242/dmm.049816 Text en © 2023. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Scelsi, Hailee F.
Hill, Kamisha R.
Barlow, Brett M.
Martin, Mackenzie D.
Lieberman, Raquel L.
Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability
title Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability
title_full Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability
title_fullStr Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability
title_full_unstemmed Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability
title_short Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability
title_sort quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9844228/
https://www.ncbi.nlm.nih.gov/pubmed/36579626
http://dx.doi.org/10.1242/dmm.049816
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