Expression of Deletion-Containing Dystrophins in mdx Muscle: Implications for Gene Therapy and Dystrophin Function

Abstract

The expression of full-length dystrophin and various dystrophin deletion mutants was monitored in rndx mouse muscle after intramuscular injection of dystrophin-encoding plasmid DNAs. Recombinant dystrophin proteins, including those lacking either the amino terminus, carboxyl terminus, or most of the central rod domain, showed localization to the plasma membrane. This suggests that there are multiple attachment sites for dystrophin to the plasma membrane. Only those constructs containing the carboxyl terminus were able to stabilize dystrophin-associated proteins (DAP) at the membrane, consistent with other studies that suggest that this domain is critical to DAP binding. Colocalization with DAP was not necessary for membrane localization of the various dystrophin molecules. However, stabilization and co-localization of the DAP did seem to be a prerequisite for expression andlor stabilization of mutant dystrophins beyond 1 wk and these same criteria seemed important for mitigating the histopathological consequences of dystrophin deficiency.

Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses

“…4a,b) of many fibres, including ones that were not obviously regenerating. These results are consistent with previous observations that the β-Dg binding region of dystrophin is necessary for stable dystrophin expression 21 and its absence results in the depletion of β-Dg and the sarcoglycans with a severe dystrophic phenotype 22 . Utrophin, which is normally restricted to myoneural synapses, was reduced ( Fig.…”

Zebrafish models flex their muscles to shed light on muscular dystrophies

“…Dystrophin is also absent from many fibres in dystroglycan-deficient chimaeric mice (Côté et al, 1999), and deletion of the β-dystroglycan-binding region in dystrophin leads to loss of dystroglycan (Fritz et al, 1995; Rafael et al, 1996), reinforcing the notion that dystrophin and the dystroglycans are necessary for the assembly and stability of the DGC.…”

Functional Rescue of the Sarcoglycan Complex in the BIO 14.6 Hamster Using δ-Sarcoglycan Gene Transfer

“…We thank Valé rie Allamand for rabbit 229 antibody. (Acsadi et al, 1991;Danko et al, 1993;Fritz et al, 1995). The incision We acknowledge Rachelle Crosbie and Michael Henry for helpful was closed with 3-4 sutures.…”

“…Furthermore, fibers with persistent The dystrophin-glycoprotein complex (DGC) is a large sarcoglycan expression lack two characteristic features oligomeric complex of sarcolemmal proteins and glycoof disease progression. First, myofibers expressing ␦-SG proteins in skeletal and cardiac muscle (reviewed in exhibit a dramatic decrease in centralized nuclei, sug -Campbell, 1995;Ozawa et al, 1995). This complex congesting that the sarcoglycan complex provides protective effects against degeneration of muscle fibers and sists of dystrophin, a large cytoskeletal protein that subsequent rounds of regeneration.…”