The ties that bind: functional clusters in limb-girdle muscular dystrophy

Abstract

The limb-girdle muscular dystrophies (LGMDs) are a genetically pleiomorphic class of inherited muscle diseases that are known to share phenotypic features. Selected LGMD genetic subtypes have been studied extensively in affected humans and various animal models. In some cases, these investigations have led to human clinical trials of potential disease-modifying therapies, including gene replacement strategies for individual subtypes using adeno-associated virus (AAV) vectors. The cellular localizations of most proteins associated with LGMD have been determined. However, the functions of these proteins are less uniformly characterized, thus limiting our knowledge of potential common disease mechanisms across subtype boundaries. Correspondingly, broad therapeutic strategies that could each target multiple LGMD subtypes remain less developed. We believe that three major "functional clusters" of subcellular activities relevant to LGMD merit further investigation. The best known of these is the glycosylation modifications associated with the dystroglycan complex. The other two, mechanical signaling and mitochondrial dysfunction, have been studied less systematically but are just as promising with respect to the identification of significant mechanistic subgroups of LGMD. A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.

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