ANO5 in Muscle Health and Disease

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PROJECT SUMMARY Mutations in ANO5 have been linked to several human diseases including muscular dystrophy. Ano5 is an intracellular membrane protein, belonging to the anoctamin protein family. Many of the proteins in this family have been found to possess the Ca2+-activated phospholipid scrambling activity. Despite the clear genetic linkage between ANO5 and muscular dystrophy in patients, we found that complete KO of Ano5 in mice showed no overt muscle pathology during our last funding period. This was independently confirmed by other investigators using a different line of complete Ano5-KO mice. These findings indicate that a potential compensatory mechanism, likely through other anoctamin proteins, is involved in minimizing the impact of complete Ano5 deficiency. Intriguingly, an Ano5-KO mouse expressing putatively a truncated Ano5 peptide developed clinical signs of muscular dystrophy with intracellular aggregates and defective membrane repair. Many of the ANO5 mutations associated with human muscular dystrophy are premature termination mutations. These findings raise an interesting question about how ANO5 mutations cause muscle degeneration in human patients: does the expression of mutant amino-terminal Ano5 peptide lead to muscular dystrophy by promoting the formation of intracellular aggregates and compromising membrane repair machinery? Our continuing research in this proposal is centered on determining the fundamental role of the amino-terminus of Ano5 in regulating the intrinsic lipid scrambling function of anoctamins proteins, membrane repair and its contribution to the pathogenesis of muscular dystrophy caused by ANO5 mutations. Moreover, our studies will reveal the compensatory mechanism underlying the lack of muscular dystrophy phenotype in complete Ano5-KO mice. Through the use of in vivo CRISPR gene editing, biochemical, histopathological, and living cell imaging studies with animal models, our planned experiments shall advance our understanding of the physiological and pathological roles of amino-terminal Ano5 peptides in muscle and also shed critical insights into the development of novel therapeutic strategies for the treatment of Ano5-related muscular dystrophy.