Protein O-Mannose Kinase-mediated regulation of α-dystroglycan function

Protein O-Mannose Kinase (POMK) is required for formation of a full-length sugar chain on the cell-surface protein α-Dystroglycan (α-DG). This sugar chain enables muscle fibers to adhere to their surrounding environment, the extracellular matrix (ECM). Eighteen enzymes are required for formation of the sugar chain enabling α-DG function. Mutations in these enzymes which completely eliminate their activity and, subsequently, α-DG function, cause Walker-Warburg Syndrome (WWS), a severe degenerative muscle disorder accompanied by structural brain and eye defects in which patients die within a few days of birth. Patients with such mutations in POMK live past this period. I identified a patient with a POMK mutation who survived to 2.5 years of age. Interestingly, muscle from the patient lacked all POMK activity but adhered weakly to the ECM protein, laminin. Mice with a muscle-specific loss of POMK demonstrated mild muscle degeneration, and their muscle could adhere weakly to laminin, similar to the patient muscle. Studies in cells lacking POMK expression demonstrated that this partial adherence was due to α-DG modified with a new, short sugar chain. This new, short sugar chain enabled the patient muscle to partially adhere to the ECM and led to a milder form of disease than WWS, enabling the patient to survive past infancy. My results demonstrate that POMK is required for formation of the full-length sugar chain on α-DG that enables its adherence to the ECM; however, in the absence of POMK, a shorter sugar chain, enabling partial adherence, is instead built.