7SKE

Myocilin OLF mutant R296H

7SKE の概要

• エントリーDOI: 10.2210/pdb7ske/pdb
• 分子名称: Myocilin, C-terminal fragment, GLYCEROL, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: olfactomedin, beta-propeller, cell adhesion
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31609.38

構造登録者

Scelsi, H.S.,Barlow, B.M.,Lieberman, R.L. (登録日: 2021-10-20, 公開日: 2023-01-11, 最終更新日: 2024-11-06)

主引用文献

Scelsi, H.F.,Hill, K.R.,Barlow, B.M.,Martin, M.D.,Lieberman, R.L.
Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability.
Dis Model Mech, 16:-, 2023

PubMed 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.

PubMed: 36579626
DOI: 10.1242/dmm.049816

実験手法

X-RAY DIFFRACTION (1.24 Å)