Uribe Mary Luz, Martín-Nieto José, Quereda Cristina, Rubio-Fernández Marcos, Cruces Jesús, Janssen George M C, de Ru Arnoud H, van Veelen Peter A, Hensbergen Paul J
Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03080 Alicante, Spain.
J Proteome Res. 2021 Jun 4;20(6):3268-3277. doi: 10.1021/acs.jproteome.1c00126. Epub 2021 May 23.
Mutations in the 1 gene, encoding a protein -mannosyltransferase essential for α-dystroglycan (α-DG) glycosylation, are frequently observed in a group of rare congenital muscular dystrophies, collectively known as dystroglycanopathies. However, it is hitherto unclear whether the effects seen in affected patients can be fully ascribed to α-DG hypoglycosylation. To study this, here we used comparative mass spectrometry-based proteomics and immunofluorescence microscopy and investigated the changes in the retina of mice in which 1 is specifically knocked out in photoreceptor cells. Our results demonstrate significant proteomic changes and associated structural alteration in photoreceptor cells of 1 cKO mice. In addition to the effects related to impaired α-DG -mannosylation, we observed morphological alterations in the outer segment that are associated with dysregulation of a relatively understudied POMT1 substrate (KIAA1549), BBSome proteins, and retinal stress markers. In conclusion, our study provides new hypotheses to explain the phenotypic changes that are observed in the retina of patients with dystroglycanopathies.
编码对α- dystroglycan（α-DG）糖基化至关重要的蛋白质-甘露糖基转移酶的1基因发生突变，在一组罕见的先天性肌营养不良症中经常被观察到，这些疾病统称为肌聚糖病。然而，迄今为止尚不清楚在受影响患者中看到的影响是否可以完全归因于α-DG低糖基化。为了研究这一点，我们在这里使用基于比较质谱的蛋白质组学和免疫荧光显微镜，并研究了在光感受器细胞中特异性敲除1的小鼠视网膜中的变化。我们的结果表明，1基因敲除小鼠的光感受器细胞中存在显著的蛋白质组学变化和相关的结构改变。除了与α-DG甘露糖基化受损相关的影响外，我们还观察到外段的形态改变，这些改变与研究相对较少的POMT1底物（KIAA1549）、BBSome蛋白和视网膜应激标志物的失调有关。总之，我们的研究提供了新的假设来解释在肌聚糖病患者视网膜中观察到的表型变化。
