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Abstract
Dysferlinopathies are a group of muscular dystrophies caused by recessive mutations in the DYSF gene encoding the dysferlin protein. Dysferlin is a transmembrane protein involved in several muscle functions like T-tubule maintenance and membrane repair. In 2009, a study showed the existence of fourteen dysferlin transcripts generated from alternative splicing. We were interested in dysferlin transcripts containing the exon 40a, and among them the transcript 11 which contains all the canonical exons and exon 40a. This alternative exon encodes a protein region that is cleaved by calpains during the muscle membrane repair mechanism. Firstly, we tested the impact of mutations in exon 40a on its cleavability by calpains. We showed that the peptide encoded by the exon 40a domain is resistant to mutations and that calpains cleaved dysferlin in the first part of DYSF exon 40a. To further explore the implication of this transcript in cell functions, we performed membrane repair, osmotic shock, and transferrin assay. Our results indicated that dysferlin transcript 11 is a key factor in the membrane repair process. Moreover, dysferlin transcript 11 participates in other cell functions such as membrane protection and vesicle trafficking. These results support the need to restore the dysferlin transcript containing the alternative exon 40a in patients affected with dysferlinopathy.
Highlights
Dysferlinopathies are disabling muscle disorders caused by recessive mutations in the DYSF gene (MIM# 603009, 2p13, GenBank NM_003494.3) encoding the dysferlin protein
This activation led to dysferlin cleavage by calpains within exon 40a, releasing a C-terminal fragment named dysferlinC72 which is recruited to membrane injury sites
The presence of four predicted pathogenic variants in databases, even if they have not been validated by functional tests, supports our belief that pathogenic mutations in this exon may exist. All these results indicate that dysferlin transcript 1 and dysferlin transcript 11 have an important role in myocyte homeostasis
Summary
Dysferlinopathies are disabling muscle disorders caused by recessive mutations in the DYSF gene (MIM# 603009, 2p13, GenBank NM_003494.3) encoding the dysferlin protein. Dysferlinopathies exist in two different forms of muscular dystrophies namely LGMD2B/R2 (LGMD2B; MIM# 253601) and Miyoshi Myopathy (MM; MIM# 254130) (Bashir et al, 1998). The main muscle groups affected at onset are proximal muscles in LGMD2B and distal muscles in MM (Liu et al, 1998). Elevated serum levels of creatine kinase, severe muscle inflammation and muscle weakness are characteristic of dysferlinopathies patients. There is no cure for these patients but several therapeutic strategies are currently under development like gene therapy
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