A.I.4: Protein aggregate myopathies: The many faces of an expanding disease group

Abstract

Pathological protein aggregates are the characteristic feature in a wide variety of human diseases affecting the central and peripheral nervous system, eyes, skin, liver as well as heart and skeletal muscles. Protein aggregate myopathies (PAM) are an emerging and numerically significant group of hereditary and acquired striated muscle diseases with marked clinical and genetic heterogeneity. Their disease manifestation varies from the neonatal period to late adulthood. They are present in diverse ethnic groups, affect both sexes, and their clinical presentation ranges from congenital myopathies over scapuloperoneal and oculopharyngeal phenotypes to distal, limb girdle, and generalized patterns of muscle weakness and wasting. PAM are due to mutations in genes coding for cytoskeletal proteins, which are either components of the myofibrillar apparatus (α-actin, myosins, titin, filamin C, myotilin, ZASP, BAG-3, FHL1) or the three-dimensional filamentous extrasarcomeric network (desmin, plectin). In addition, mutations in genes coding for proteins with essential functions in protein quality control (VCP, DNAJB6, BAG-3, aB-crystallin), selenoproteins (selenoprotein N), and DNA-binding proteins (PABPN1) have been described. Exciting novel insight into the molecular pathogenesis of PAM lead to concepts in which PAM-related gene defects cause effects at multiple levels by influencing the structure and function of motor proteins, sarcomeric and extrasarcomeric cytoskeleton proteins, signaling cascades, protein quality control systems as well as the function of cell organelles in striated muscle cells. The presentation will give an overview on the clinical, myopathological and pathophysiological aspects of PAM. In addition, central results from the analysis of novel cell and animal models, the implementation of a PAM patient registry and a pilot study for the treatment of PAM will be highlighted. Pathological protein aggregates are the characteristic feature in a wide variety of human diseases affecting the central and peripheral nervous system, eyes, skin, liver as well as heart and skeletal muscles. Protein aggregate myopathies (PAM) are an emerging and numerically significant group of hereditary and acquired striated muscle diseases with marked clinical and genetic heterogeneity. Their disease manifestation varies from the neonatal period to late adulthood. They are present in diverse ethnic groups, affect both sexes, and their clinical presentation ranges from congenital myopathies over scapuloperoneal and oculopharyngeal phenotypes to distal, limb girdle, and generalized patterns of muscle weakness and wasting. PAM are due to mutations in genes coding for cytoskeletal proteins, which are either components of the myofibrillar apparatus (α-actin, myosins, titin, filamin C, myotilin, ZASP, BAG-3, FHL1) or the three-dimensional filamentous extrasarcomeric network (desmin, plectin). In addition, mutations in genes coding for proteins with essential functions in protein quality control (VCP, DNAJB6, BAG-3, aB-crystallin), selenoproteins (selenoprotein N), and DNA-binding proteins (PABPN1) have been described. Exciting novel insight into the molecular pathogenesis of PAM lead to concepts in which PAM-related gene defects cause effects at multiple levels by influencing the structure and function of motor proteins, sarcomeric and extrasarcomeric cytoskeleton proteins, signaling cascades, protein quality control systems as well as the function of cell organelles in striated muscle cells. The presentation will give an overview on the clinical, myopathological and pathophysiological aspects of PAM. In addition, central results from the analysis of novel cell and animal models, the implementation of a PAM patient registry and a pilot study for the treatment of PAM will be highlighted.