Wild Type Mouse
MMex38 Mouse
14 month old healthy Psoas muscle
14 month old dysferlin-deficient Psoas muscle
What is Dysferlin?
Dysferlin is a member of the “Ferlin” protein family. What they share is their feature of containing 6 Ca2+domains (Ca2+ binding domain is a protein structural domain involved in targeting proteins to cell membranes). These domains were originally identified in protein kinase C as being responsible for the calcium-dependent binding of phospholipids.
Dysferlin plays a crucial role in skeletal muscle fiber membrane repair, and is key to maintaining the function and integrity of muscle tissue, especially after exercise or injury.
missense mutants
Dysferlinopathy
Dysferlinopathy is caused by inherited genetic mutations in the gene for dysferlin. It encompasses a range of muscle disorders, which are primarily classified into two major phenotypes: Miyoshi muscular dystrophy (MMD) and limb-girdle muscular dystrophy type 2B (LGMD2B), which is studied at this lab. It also includes two less common phenotypes: asymptomatic hyperCKemia and Distal Myopathy with Anterior Tibial onset (DMAT).
Sodium 4-Phenylbutyric Acid (4-PBA):
Sodium 4-phenylbutyric acid (4-PBA), is a phenol conjugated short-chain fatty acid. We have established that the clinically approved drug (4-PBA), used for the treatment of patients with Urea Cycle Disorders, 4-PBA is efficacious in restoring a number of patient missense mutations, including hDYSFL1341P (the patient mutation), to the plasma membrane of HEK cells and GREG mouse myoblast and GREG myofibers.
Moreover, 4-PBA treatment of GREG myofibers expressing hDYSFL1341P restores membrane repair capacity of otherwise repair deficient cells. Based on these results, we hypothesize that 4-PBA likely acts as a chemical chaperone, one of its known activities, stabilizing misfolded mutant dysferlin proteins preventing their destruction and allowing them safe passage within the endomembrane system allowing for membrane localization and functional restoration of membrane repair.
