The muscular dystrophies are a heterogeneous group of inherited disorders featuring progressive muscle weakness and atrophy. After the discovery of dystrophin, remarkable progress was made in defining the molecular properties of various proteins involved in the muscular dystrophies. As a result, we now have some understanding of the dystrophinassociated protein complex and its importance as a cell membrane scaffold that provides structural stability to muscle cells [1]. While the muscular dystrophies linked to loss of dystrophin function and its associated proteins are caused by diminished membrane integrity, another class of dystrophies can arise because of a diminished capacity for rapid muscle membrane repair after injury. Dysferlin was the first identified member of a putative muscle-specific repair complex that permits rapid resealing of membranes disrupted by mechanical stress. Membrane resealing is a function conserved by most cells and is mediated by a mechanism closely resembling regulated Ca-dependent exocytosis. A primary role for dysferlin in this pathway, as a Ca-regulated “fusogen”, has been suggested, and a number of candidate partner proteins have been identified. Considerable advances have been made in our understanding of dysferlin and its role in membrane repair, signaling, muscle physiology, and pathophysiology [2]. Dysferlin is a homologue of the Caenorhabditis elegans fer-1 gene, which mediates vesicle fusion to the plasma membrane in spermatids. This evidence and other inferences suggested that dysferlin is important in mediating organelle fusion with sites of breached skeletal muscle plasma membrane. Bansal et al. [3], from the laboratory of Kenneth Campbell, showed that dysferlin-gene-deleted mice maintain a functional dystrophin–glycoprotein complex but nevertheless develop a progressive muscular dystrophy. They observed that in normal muscle, membrane patches enriched in dysferlin were detected in response to sarcolemma injuries. In contrast, there were sub-sarcolemmal vesicular accumulations in dysferlin-gene-deficient muscle. The group used membrane repair assays with a two-photon laser-scanning microscope and demonstrated that wild-type muscle fibers efficiently resealed their sarcolemma in the presence of Ca. In stark contrast, dysferlin-deficient muscle fibers were defective in Cadependent sarcolemma resealing. The work showed that membrane repair is an active process in skeletal muscle fibers and that dysferlin has an essential role in this process. The findings from the Campbell laboratory showed that disruption of the muscle membrane repair machinery was responsible for dysferlin-deficient muscle degeneration. The group highlighted the importance of this basic cellular mechanism of membrane resealing in human disease. Lammerding and Lee [4] provided a short overview. A naive version of what might be happening is offered in Fig. 1. In man, dysferlin deficiency leads to three types of clinically distinct muscular dystrophy forms, namely, limbgirdle musclar dystrophy type 2B, Miyoshi myopathy, and distal myopathy with anterior tibial onset. Dysferlindeficient mice develop analogous conditions. There is plenty of dysferlin expressed in the heart; however, cardiomyopathy in humans with dysferlin mutations has not been previously characterized. Nevertheless, a 57-yearold Japanese woman was recently reported as having ventricular dilatation and diffuse hypokinesia, consistent with cardiomyopathy [5]. The Campbell laboratory thus pursued the possibility that mutations in dysferlin might J Mol Med (2007) 85:1157–1159 DOI 10.1007/s00109-007-0252-8
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