Three different novel, homozygous mutations in CAPN1 were found: c.2118+1G > T, c.397C > T, c.843+1G > C. The patient with the earliest onset also manifested profound muscle weakness, likely related to a second homozygous mutation in DYSF (dysferlinopathy).
These findings suggest that increasing the amount of misfolded dysferlin using small molecules could represent an effective future clinical treatment for dysferlinopathy.
Defects in the gene coding for dysferlin, a membrane-associated protein, affect many tissues, including skeletal muscles, with a resultant myopathy called dysferlinopathy.
This dysferlin-deficient cell line should allow the study of pathophysiological pathways involved in dysferlin-deficient muscle and constitute a tool for high-throughput screening of therapeutic compounds for patients with dysferlinopathy and other muscle diseases.
Our finding of a truncating dysferlin mutation confirmed dysferlinopathy in this family and we propose that the single mutant allele is the primary contributor to the neuromuscular symptoms seen in the second-generation pauci-symptomatic carriers.
<b>Conclusions</b>: Our findings provide evidence that exosomes are efficient carriers of dysferlin and can be employed for the treatment and non-invasive diagnosis of dysferlinopathy.
In this article, we outline a simple two-photon laser wounding protocol for assessing cell membrane repair in vitro in both healthy and dysferlinopathy patient fibroblast cells transfected with or without a full-length dysferlin plasmid.
In the absence of dysferlin, skeletal muscle cells fail to reseal properly after injury, resulting in slow progress of the dysferlinopathy muscular dystrophy (MD).
These preclinical data are the first report of a smaller dysferlin variant tailored for AAV single particle delivery that restores motor function and, therefore, represents an attractive candidate for the treatment of dysferlinopathy.
Dysferlinopathy is characterized by absence or marked reduction of dysferlin protein with 43% of reported pathogenic variants being missense variants that span the length of the dysferlin protein.
Additional findings of histopathology, specific stain for sarcolemmal membrane protein, Western blot analysis and clinical presentation clinched the diagnosis further of dysferlinopathy (LGMD2B) in both our patients.
The dysferlin protein's functions and dysferlinopathy disease pathogenesis are not fully explored, and there is no specific treatment available that can alter the disease progression.