WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome.
WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome.
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DOI：
10.1136/jmedgenet-2020-107257
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发表时间：
2022-01
影响因子：
4
通讯作者：
Barrett T
中科院分区：
文献类型：
--
作者：
Hu K;Zatyka M;Astuti D;Beer N;Dias RP;Kulkarni A;Ainsworth J;Wright B;Majander A;Yu-Wai-Man P;Williams D;Barrett T
Wolfram 综合征 (WFS) 是一种罕见疾病，其特征是儿童期发病的糖尿病和进行性视神经萎缩。大多数患者的 WFS1 基因存在变异。我们对 WFS1 变体进行了功能研究，并将其与 WFS1 蛋白表达和表型相关联。对 9 名临床诊断为 WFS 的患者进行了内质网 (ER) 应激标记定量 PCR 和成纤维细胞蛋白提取物免疫印迹研究以检测 WFS1 蛋白表达。荧光素酶报告基因测定用于评估 ATF-6 依赖性未折叠蛋白反应 (UPR) 激活。 6 名 WFS1 复合杂合无义突变患者未检测到 WFS1 蛋白表达； 3 名具有错义变异的患者的 WFS1 蛋白表达分别为 4%、45% 和 48%。其中一个也有 OPA1 突变，被重新分类为常染色体显性视神经萎缩综合征。 ER 应激标志物 mRNA 和 WFS1 蛋白表达之间不存在相关性。 ERSE-荧光素酶报告基因显示两名测试患者的 UPR ATF6 分支被激活。与不表达 WFS1 的患者（登记为严重视力受损）相比，部分 WFS1 表达的患者表现出较轻微的视力受损（无症状或仅色盲）（p=0.04）。在调整视神经萎缩的持续时间后，这些差异仍然存在。部分 WFS1 蛋白表达的 WFS 患者表现出较轻微的视力障碍。这表明部分 WFS1 蛋白表达对视力障碍的严重程度和可能的进展具有保护作用，并且增加残余 WFS1 蛋白表达的治疗可能是有益的。
Wolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype. 9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation. 6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy. Patients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.
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