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.