From bedside to bench: A multimodal approach uncovering the molecular basis of the MYBPC1-linked Myotrem myopathy

Abstract Myotrem, a congenital myopathy identified in 2019, is linked to dominant variants in the pivotal M-domain of slow-skeletal Myosin Binding Protein-C (sMyBP-C), mediating muscle contractility. However, our understanding of the disease pathogenesis and etiologies remains limited. Using a multimodal approach integrating clinical, biophysical, structural, and computational findings, we uncover the structure and properties of the slow-skeletal M-domain—the Myotrem hotspot—while deciphering the impact of the c.795_803dup p.(Leu266_Arg268dup) variant at the molecular and atomic levels. As current treatments are restricted to