P.15.4 ZASP–sZM mutations in myofibrillar myopathy cause skeletal muscle Z-disc disruption by disassembling α-actinin cross-linked skeletal actin filaments

Abstract

Myofibrillar myopathies (MFM) are characterized by early and prominent disruption of the Z-disc with focal dissolution of myofibrils and ectopic accumulation of myofibrillar proteins. The molecular mechanisms underlying the Z-disc disruption in MFM are not yet delineated. The Z-disc is a key element for structural integrity of the sarcomere, the basic contractile unit in skeletal muscle. The core of the Z-disc consists of actin filaments (F-actin) from adjacent sarcomeres cross-linked by α-actinin. We explored the mechanism of skeletal muscle Z-disc disruption in zaspopathy, a prototype MFM caused by ZASP mutations (A147T and A165V) at or within a highly conserved motif (sZM) that is expressed in striated muscle. Our studies show that ZASP is a novel skeletal actin binding protein and that the sZM domain is important for ZASP-actin interaction in skeletal muscle. Both wild type and mutant ZASP interact with skeletal actin, but only mutant proteins cause disassembly of actinin-crosslinked F-actin in vitro and the Z-disc disruption with F-actin accumulation in electroporated mouse skeletal muscle, as in the human disease. These results show that ZASP–sZM mutations have deleterious effects on the core structure of the Z-discs in striated muscle and support a toxic gain-of-function disease mechanism. Other MFM gene products (myotilin, desmin, BAG3, αβ-Crystallin, and filamin C) are known to regulate the organization and stability of F-actin in skeletal muscle. It is possible that the molecular pathways leading to skeletal muscle Z-disc disruption are shared by these myopathies. Alteration of F-actin dynamics, by either direct or indirect association of mutant proteins with actin filaments, may emerge as a unifying disease mechanism in this group of degenerative myopathies.