Limb girdle muscular dystrophy type R1/2A (LGMD R1/2A) is caused by mutations in the Ca2+-dependent
cysteine protease, Calpain 3 (CAPN3). It is the most common form of autosomal recessive LGMD and accounts
for ~30% of all LGMD cases. While the disease is characterized by progressive skeletal muscle weakness in
proximal limbs, the onset, severity, and progression are highly variable. Much of the variation stems from the fact
that >200 mutations in CAPN3 can lead to loss-of-protein, loss-of-function, or dysregulated function dependent
upon the site of mutation. Importantly, a comprehensive understanding of CAPN3 function has not been
achieved, even with the advent of gene therapies tailored to restore CAPN3 specifically in skeletal muscle.