Disease relevance of Dysf

• Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B [1].
• Defective membrane repair in dysferlin-deficient muscular dystrophy [2].
• Mutations in dysferlin are linked to two clinically distinct muscle diseases, limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, but the mechanism that leads to muscle degeneration is unknown [2].
• Simultaneous dystrophin and dysferlin deficiencies associated with high-level expression of the coxsackie and adenovirus receptor in transgenic mice [3].
• Humans with mutations in dysferlin ( DYSF ) develop muscle weakness that affects both proximal and distal muscles [4].
• We demonstrate that dysferlin is also involved in cardiomyocyte membrane repair and that dysferlin deficiency leads to cardiomyopathy [5].

High impact information on Dysf

• Membrane repair is therefore an active process in skeletal muscle fibres, and dysferlin has an essential role in this process [2].
• In normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma injuries [2].
• Cav3R26Q and other Golgi-associated mutants of both Cav-3 (Cav3P104L) and Cav-1 (Cav1P132L) caused a dramatic redistribution of dysferlin to the Golgi complex [6].
• Heterologously expressed epitope-tagged dysferlin associates with the plasma membrane in primary fibroblasts and muscle cells [6].
• Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency [7].

Chemical compound and disease context of Dysf

• It is the first known example of a C2 domain containing protein involved in a muscular dystrophy, mutations in the gene can be involved in a variable phenotype, and a naturally occurring mouse model for dysferlin deficiency has recently been identified [8].

Biological context of Dysf

• Therefore, all studies involving the A/J mice or mice derived from A/J, including recombinant inbred, recombinant congenic and chromosome substitution strains, should take into account the dysferlin defect in these strains [7].
• The distribution of the annexins and the efficiency of sarcolemmal wound-healing are significantly disrupted in dysferlin-deficient muscle [9].
• Up-regulation of MHC class I expression accompanies but is not required for spontaneous myopathy in dysferlin-deficient SJL/J mice [10].
• A dysferlin point mutation responsible for muscular dystrophy was engineered into the dysferlin C2A domain and demonstrated reduced calcium-sensitive phospholipid binding [11].
• We investigated the pattern of dysferlin and myoferlin expression in a cell culture model of muscle development and found that dysferlin is expressed in mature myotubes [11].

Anatomical context of Dysf

• In contrast, myoferlin is highly expressed in elongated "prefusion" myoblasts and is decreased in mature myotubes where dysferlin expression is greatest [11].
• Myoferlin is highly homologous to dysferlin and like dysferlin is a plasma membrane protein with six C2 domains highly expressed in muscle [11].
• Subcellular membrane fractionation revealed that a portion of dysferlin associated with a T-tubule-enriched intracellular membrane fraction as well as a sarcolemmal fraction [12].
• In this model, myoblasts do not fuse into myotubes and we found that dysferlin expression is reduced [13].
• Dysferlin is expressed in skeletal and cardiac muscles [14].

Associations of Dysf with chemical compounds

• We found that C2A, the first C2 domain of dysferlin and myoferlin, bound 50% phosphatidylserine and that phospholipid binding was regulated by calcium concentration [11].
• Intracellular localization of dysferlin and its association with the dihydropyridine receptor [12].
• We describe the alteration of dysferlin expression and localization in skeletal muscle from a patient with raised serum creatine kinase (hyperCKaemia), whose reduction of caveolin 3 is caused by a CAV3 P28L mutation [13].

Physical interactions of Dysf

• These results demonstrated that dysferlin may be involved in the formation of an oligomeric complex with DHPR and caveolin-3 [12].

Other interactions of Dysf

• We also found that caveolin-3, previously shown to interact with dysferlin, coprecipitates with DHPR [12].

Analytical, diagnostic and therapeutic context of Dysf

• Here, we report two novel lines of dysferlin-deficient mice obtained by (a) gene targeting and (b) identification of an inbred strain, A/J, bearing a retrotransposon insertion in the dysferlin gene [7].
• Co-immunofluorescence, co-immunoprecipitation, and fluorescence lifetime imaging microscopy revealed that dysferlin normally associates with both annexins A1 and A2 in a Ca2+ and membrane injury-dependent manner [9].
• The transcriptomes of proximal and distal muscles from wildtype C57BL/10 and dysferlin deficient C57BL/10.SJL-Dysf mice at a prepathological stage were assessed using the Affymetrix oligonucleotide-microarray system [15].
• Immunohistochemistry confirmed granular cytoplasmic expression pattern of dysferlin in muscle fibers [12].
• Dysferlin expression after normal myoblast transplantation in SCID and in SJL mice [16].

References