Muscular dystrophies comprise a group of genetically determined disorders that cause progressive weakness and wasting of skeletal muscle. Since the discovery of dystrophin, a large number of genes either associated with or linked to various types of muscular dystrophies have been identified, thus providing a genetic basis for their classification. Dysferlin was identified as a gene mutated in three pathologies: LGMD2B (limb-girdle muscular dystrophy), MM (Miyoshy myopathy) and MDAT (muscular dystrophy of anterior tibialis). Caused by the same mutations, these disorders are characterized by the involvement of different type of affected muscles. Recent work suggests the function of dysferlin in membrane repair and demonstrates that defective membrane repair is a novel mechanism of muscle regeneration. To better characterize the muscle dysferlin protein complex, we performed a yeast two hybrid screening using as bait the dysferlin cDNA, divided in six overlapping fragments, to screen a human muscle cDNA library. This assay gave us the possibility to identify muscle specific dysferlin interacting proteins. We retrieved interactions with several proteins involved in different muscular pathways, such as myofibrillogenesis or proteins involved in structural functions. We show that the sarcomeric Z-line component T-CAP (also called telethonin) binds the C-terminal domain of dysferlin. This interaction was also confirmed by in vivo binding assay and immunofluorescence studies, using different cellular system (COS-7, HeLa, C2C12 cells). Together with previous data on the colocalization and interaction of T-CAP with the α-subunit of the potassium current (Iks) channel MinK, these data may suggest that T-CAP functions as an adapter protein to link together myofibrillar components with the membranous proteins. We speculate that this interaction may contribute to a stretch-dependent regulation of ionic flux in muscle, providing a “mechano-electrical feedback” system.

Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetically determined disorders classified on the basis of common clinical features. They all share primary and predominant affection of proximal musculature of the pelvic and shoulder girdles. Clinical course is characterized by great variability ranging from severe forms with rapid progression to very mild forms.