Mutations in protein O-glucosyltransferase 1 (POGLUT1) cause a recessive form of limb-girdle muscular dystrophy (LGMD-R21) associated with reduced satellite cell number and NOTCH1 signaling in adult patient muscles and impaired myogenic capacity of patient-derived muscle progenitors. Here, POGLUT1 is linked to limb-girdle muscular dystrophy.