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

Abstract

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.

The genetic background of hydrocephalus in a population-based cohort: implication of ciliary involvement

“…88 Defective interaction with the extracellular matrix also interferes with Sonic Hedgehog and Notch signalling. 89,90 Therefore, several of the genes with PTVs may indirectly affect cilia-dependent processes in neurogenesis: B3GALNT2 encodes an enzyme essential for the correct glycosylation of α-DG, which impairs the interaction of α-DG with extracellular matrix elements, 51,[91][92][93][94][95] possibly disrupting the signalling functions of primary cilia. The genes DAG1, and NF1 are involved in the regulation of neuronal or astrocytic differentiation of neural stem/progenitor cells, processes regulated by primary cilia.…”