Limb-girdle muscular dystrophy type 2I (LGMD2I) constitutes 40% of the limb-girdle muscular dystrophies in Denmark. All patients carry the founder mutation, L276I, on at least one allele of the fukutin-related protein gene (FKRP). Patients homozygous for the L276I aberration generally have a mild phenotype, while patients compound heterozygous for L276I invariably have a severe phenotype. In order to understand the mechanisms leading to progressive dystrophy in these patients, we have developed a mouse model with the L276I mutation. We generated a FKRP L276I knock-in mouse model, a heterozygous FKRP knock-out model using a cre-lox system, and by mating these, a hemizygous L276I knock-in/FKRP knock-out model to mimick the compound heterozygous LGMD2I patients with the L276I mutation. We found that the FKRP L276I knock-in was viable, fertile and with no overt sign of muscular dystrophy. However, we noticed a significant increase in muscle regeneration in animals 12 and 20months old compared to controls, indicating that the L276I mutation in FKRP leads to progressive myopathic changes. The L276I hemizygous mouse model did not display any significant myopathy at the age of 6months. Using the hemizygous FKRP L276I/− model to generate homozygous FKRP knock-out mice did not yield any live births, and recovering all embryos from the mating of this model to embryonic stage E9.5 did not yield any FKRP knock-out embryos, suggesting that this is embryonically lethal. Unlike LGMD2I patients with the L276I substitution, the FKRP L276I/L276I mouse model displays only modest myopathic changes. This, and the non-affected hemizygous FKRP L276I/– model, suggest that the FKRP L276I mutation in mice either does not affect the basic properties of FKRP much, or the FKRP dynamics in mice are different from that in humans. Absence of FKRP is, however, embryonically lethal.