Portrait of Dysferlinopathy: Diagnosis and Development of Therapy

Abstract

Dysferlinopathy is a disease caused by a dysferlin deficiency due to mutations in the DYSF gene. Dysferlin is a membrane protein in the sarcolemma and is involved in different functions, such as membrane repair and vesicle fusion, T-tubule development and maintenance, Ca²⁺ signalling, and the regulation of various molecules. Miyoshi Myopathy type 1 (MMD1) and Limb-Girdle Muscular Dystrophy 2B/R2 (LGMD2B/LGMDR2) are two possible clinical presentations, yet the same mutations can cause both presentations in the same family. They are therefore grouped under the name dysferlinopathy. Onset is typically during the teenage years or young adulthood and is characterized by a loss of Achilles tendon reflexes and difficulty in standing on tiptoes or climbing stairs, followed by a slow progressive loss of strength in limb muscles. The MRI pattern of patient muscles and their biopsies show various fibre sizes, necrotic and regenerative fibres, and fat and connective tissue accumulation. Recent tools were developed for diagnosis and research, especially to evaluate the evolution of the patient condition and to prevent misdiagnosis caused by similarities with polymyositis and Charcot-Marie-Tooth disease. The specific characteristic of dysferlinopathy is dysferlin deficiency. Recently, mouse models with patient mutations were developed to study genetic approaches to treat dysferlinopathy. The research fields for dysferlinopathy therapy include symptomatic treatments, as well as antisense-mediated exon skipping, myoblast transplantation, and gene editing.

Keywords: LGMD2B; LGMDR2; Miyoshi myopathy; dysferlin; dysferlinopathy; therapy.

Figure 1

Dysferlin in the sarcolemma. A skeletal muscle is made of fibres. Each fibre is wrapped in a plasma membrane, the sarcolemma, which extends into T-tubules through the sarcoplasmic reticulum. The sarcoplasmic reticulum is made of cavities to stock calcium in the muscles. The sarcolemma is a membrane containing several proteins playing different roles in calcium signalization and membrane repair. Affixin binds to the C-terminal region of dysferlin and shows abnormal localization in dysferlin-deficient muscles [7]. Caveolin-3 also colocalizes with dysferlin, as well as with the dihydropyridine receptor, an L-type Ca²⁺ channel in the T-tubules [8]. Calpain-3 cleaves annexins A1 and A2, as well as AHNAK, to regulate the dysferlin complex and is Ca²⁺-dependant [9]. S100A10 forms a complex with annexin A2 and the C-terminal region of AHNAK and then binds to the dysferlin membrane complex [10]. Annexin A1 also creates a complex with protein S100A11 to join dysferlin in participating in Ca²⁺-dependant membrane repair [11]. Dysferlin also binds with tubulin with its C2A and C2B domains [12].