Retinal Proteomics of a Mouse Model of Dystroglycanopathies Reveals Molecular Alterations in Photoreceptors

Mutations in the POMT1 gene, encoding a protein O-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 Pomt1 is specifically
knocked out in photoreceptor cells. Our results demonstrate significant
proteomic changes and associated structural alteration in photoreceptor
cells of Pomt1 cKO mice. In addition to the effects
related to impaired α-DG O-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-肌营养不良蛋白聚糖（α-dystroglycan，α-DG）糖基化至关重要的蛋白O-甘露糖基转移酶（protein O-mannosyltransferase）的POMT1基因突变，常见于一组统称为肌营养不良蛋白聚糖病（dystroglycanopathies）的罕见先天性肌营养不良症中。然而，截至目前仍不清楚受累患者中观察到的病理效应是否可完全归因于α-DG糖基化不足。为探究该问题，本研究采用基于质谱的比较蛋白质组学与免疫荧光显微镜技术，对光感受器细胞中Pomt1基因特异性敲除的小鼠视网膜的变化进行了分析。本研究结果显示，Pomt1条件性敲除（cKO）小鼠的光感受器细胞中存在显著的蛋白质组学改变及相关结构异常。除了与α-DG O-甘露糖基化受损相关的效应外，本研究还观察到光感受器外节的形态学改变，该改变与研究相对较少的POMT1底物KIAA1549、BBSome蛋白以及视网膜应激标志物的表达失调相关。综上，本研究为解释肌营养不良蛋白聚糖病患者视网膜中观察到的表型改变提供了全新的假说。