Costameric integrin and sarcoglycan protein levels are altered in a<i>Drosophila</i>model for Limb-girdle muscular dystrophy type 2H
Simranjot Bawa, Samantha Gameros, Kenny Baumann, David Brooks, Joseph A Kollhoff, Michal Žółkiewski, Andrea David Re Cecconi, Nicolò Panini, Massimo Russo, Rosanna Piccirillo, David K. Johnson, M.M. Kashipathy, K.P. Battaile, Scott Lovell, Samuel Bouyain, Jessica Kawakami, Erika R. Geisbrecht
Abstract
as a model. Here we show that LGMD2H disease-causing mutations in the NHL domain are molecularly and structurally conserved between fly and human TRIM32. Furthermore, transgenic expression of a subset of myopathic alleles (R394H, D487N, and 520fs) induce myofibril abnormalities, altered nuclear morphology, and reduced TRIM32 protein levels, mimicking phenotypes in patients afflicted with LGMD2H. Intriguingly, we also report for the first time that the protein levels of βPS integrin and sarcoglycan δ, both core components of costameres, are elevated in TRIM32 disease-causing alleles. Similarly, murine myoblasts overexpressing a catalytically inactive TRIM32 mutant aberrantly accumulate α- and β-dystroglycan and α-sarcoglycan. We speculate that the stoichiometric loss of costamere components disrupts costamere complexes to promote muscle degeneration.