Browsing by Subject "Protein misfolding"

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    Biophysical, cellular, and animal models of dystrophin missense mutations
    (2014-12) Talsness, Dana
    The 427kDa protein dystrophin is expressed in skeletal muscle where it localizes to the costamere and physically links the interior of muscle fibers to the extracellular matrix. Mutations in the DMD gene encoding dystrophin lead to a severe muscular dystrophy known as Duchenne (DMD) or a mild form known as Becker (BMD). Currently, there is no cure for DMD or BMD, but there are several therapies being investigated that target specific types of mutations found in the DMD gene. Nonsense mutations almost always lead to a complete lack of dystrophin protein, with stop codon read-through drugs being studied for personalized treatments. Out-of-frame deletions and insertions also cause nearly a complete lack of dystrophin, for which exon-skipping is currently being investigated. Missense mutations in dystrophin, however, cause a wide range of phenotypic severity in patients, the molecular and cellular consequences of such mutations are not well understood, and there are no therapies currently targeting this genotype. Here, we report on three separate model systems of missense mutations in dystrophin: an in vitro biochemical model, a myoblast cell culture model, and an in vivo animal model. Together, they provide evidence that different missense mutations cause variable degrees of thermal instability, which leads to proportionally decreased dystrophin expression, and subsequently causes dystrophic phenotypes. In addition, our initial studies of small molecule treatments show that it is possible to increase the levels of mutant dystrophin, and may lead to personalized therapeutics for patients with missense mutations.