摘要：SummaryFukuyama congenital muscular dystrophy (FCMD) is a severe, intractable genetic disease that affects the skeletal muscle, eyes, and brain and is attributed to a defect in alpha dystroglycan (αDG)O-mannosyl glycosylation. We previously established disease models of FCMD; however, they did not fully recapitulate the phenotypes observed in human patients. In this study, we generated induced pluripotent stem cells (iPSCs) from a human FCMD patient and differentiated these cells into three-dimensional brain organoids and skeletal muscle. The brain organoids successfully mimicked patient phenotypes not reliably reproduced by existing models, including decreased αDG glycosylation and abnormal radial glial (RG) fiber migration. The basic polycyclic compound Mannan-007 (Mn007) restored αDG glycosylation in the brain and muscle models tested and partially rescued the abnormal RG fiber migration observed in cortical organoids. Therefore, our study underscores the importance of αDGO-mannosyl glycans for normal RG fiber architecture and proper neuronal migration in corticogenesis.Graphical abstractDisplay OmittedHighlights•FCMD muscle and brain defects result from reduced α-dystroglycan (α-DG) glycosylation•iPSC-derived brain organoids exhibit structural defects like those seen in FCMD patients•FCMD organoids exhibit decreased α-DG glycosylation and abnormal radial glial migrations•Mannan-007 partially restored α-DG glycosylation and radial glial migration defectsPathophysiology; Neuroscience; Tissue Engineering
