Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines.
Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines.
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DOI：
10.1093/hmg/ddac065
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发表时间：
2022-08-23
影响因子：
3.5
通讯作者：
Delprat, Benjamin
中科院分区：
文献类型：
--
作者：
Crouzier, Lucie;Richard, Elodie M.;Diez, Camille;Alzaeem, Hala;Denus, Morgane;Cubedo, Nicolas;Delaunay, Thomas;Glendenning, Emily;Baxendale, Sarah;Lievens, Jean-Charles;Whitfield, Tanya T.;Maurice, Tangui;Delprat, Benjamin
Wolfram综合征(WS)是一种罕见的遗传病，以糖尿病、视神经萎缩和耳聋为特征。患者在35岁时死亡，主要死于呼吸衰竭或吞咽困难。不幸的是，目前还没有阻止症状进展的治疗方法，迫切需要足够的研究模型。在这里，我们报告了两个功能缺失的斑马鱼突变系：wfs1aC825X和wfs1bW493X的表型特征。我们观察到wfs1a缺乏改变了鱼的耳朵和视网膜的大小。我们还记录了在基础状态和应激条件下，即在衣霉素处理后，未折叠蛋白反应(UPR)基因的表达水平下降。有趣的是，这两个突变体都会导致其行为测量的视觉功能下降。这些缺陷与基础和应激条件下UPR基因表达水平的降低有关。有趣的是，在wfs1b突变体中，线粒体的基础呼吸、ATP连接呼吸和最大呼吸都一过性地减少。综上所述，这些斑马鱼品系突出了wfs1a和wfs1b在UPR、线粒体功能和视觉生理学中的关键作用。这些模型将是更好地了解Wfs1的细胞功能和开发WS的新治疗方法的有用工具。
Wolfram syndrome (WS) is a rare genetic disease characterized by diabetes, optic atrophy and deafness. Patients die at 35 years of age, mainly from respiratory failure or dysphagia. Unfortunately, there is no treatment to block the progression of symptoms and there is an urgent need for adequate research models. Here, we report on the phenotypical characterization of two loss-of-function zebrafish mutant lines: wfs1aC825X and wfs1bW493X. We observed that wfs1a deficiency altered the size of the ear and the retina of the fish. We also documented a decrease in the expression level of unfolded protein response (UPR) genes in basal condition and in stress condition, i.e. after tunicamycin treatment. Interestingly, both mutants lead to a decrease in their visual function measured behaviorally. These deficits were associated with a decrease in the expression level of UPR genes in basal and stress conditions. Interestingly, basal, ATP-linked and maximal mitochondrial respirations were transiently decreased in the wfs1b mutant. Taken together, these zebrafish lines highlight the critical role of wfs1a and wfs1b in UPR, mitochondrial function and visual physiology. These models will be useful tools to better understand the cellular function of Wfs1 and to develop novel therapeutic approaches for WS.
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影响因子：
30.8
作者：
Inoue, H;Tanizawa, Y;Permutt, MA
通讯作者：
Permutt, MA
影响因子：
7.7
作者：
De Franco, Elisa;Flanagan, Sarah E.;Hattersley, Andrew T.
通讯作者：
Hattersley, Andrew T.
影响因子：
1.2
作者：
Eimre, Margus;Kasvandik, Sergo;Koks, Sulev
通讯作者：
Koks, Sulev
影响因子：
7.7
作者：
Förster D;Helmbrecht TO;Mearns DS;Jordan L;Mokayes N;Baier H
通讯作者：
Baier H
影响因子：
168.9
作者：
BARRETT, TG;BUNDEY, SE;MACLEOD, AF
通讯作者：
MACLEOD, AF