Fig. 1

Schematic diagram of proteins associated with LGMD and other muscle diseases such as DMD. When specific proteins are known to interact, they are portrayed as overlapping. The extracellular space occupies the upper portion of the diagram. The double line in the middle represents the sarcolemma. The bottom portion shows the intracellular compartments, including the sarcoplasm, sarcomere, nucleus, and mitochondria. The diverse cellular localizations of proteins associated with both recessive and dominant forms of LGMD highlight the need to organize the proteins into functional clusters that can identify common disease mechanisms and new therapeutic targets. The best known functional cluster to date is the glycosylation pathway that helps create and maintain the dystroglycan complex. The dystroglycanopathy genes include FKTN, FKRP, POMT1, POMT2, POMGnT1, POMGNT2, ISPD, and GMPPB. The postulated second functional cluster relates to mechanical signaling, which is critical for communications among the contractile apparatus, the surrounding sarcoplasm, the sarcolemma, and the extracellular matrix. The MAPK pathway has been found to be involved in numerous subtypes of LGMD. The sarcoglycan complex in particular is emerging as a key mechanosensor. Other LGMD proteins such as calpain 3 and dysferlin may be additional components of this cluster, or represent independent clusters. The postulated third functional cluster centers around mitochondrial dysfunction, which has been shown to be present in LGMD R1-R6 (LGMD2A-2F), with hints of involvement in newer LGMD genes such as PYROXD1