Abstract
Mutations in striated preferentially expressed protein kinase (SPEG), a member of the myosin light chain kinase protein family, are associated with centronuclear myopathy (CNM), cardiomyopathy, or a combination of both. Burgeoning evidence suggests that SPEG plays critical roles in the development, maintenance, and function of skeletal and cardiac muscles. Here we review the genotype-phenotype relationships and the molecular mechanisms of SPEG-related diseases. This review will focus on the progress made toward characterizing SPEG and its interacting partners, and its multifaceted functions in muscle regeneration, triad development and maintenance, and excitation-contraction coupling. We will also discuss future directions that are yet to be investigated including understanding of its tissue-specific roles, finding additional interacting proteins and their relationships. Understanding the basic mechanisms by which SPEG regulates muscle development and function will provide critical insights into these essential processes and help identify therapeutic targets in SPEG-related disorders.
Highlights
Centronuclear myopathies (CNMs) are a group of congenital myopathies characterized by clinical features of muscle weakness, increased central nuclei, and genetic heterogeneity [1]
Mutations that only affect the region unique to SPEGβ with preserved SPEGα function appear to be associated with a milder cardiomyopathy phenotype
Disease modelling of SPEG alterations in mice and iPS cells has provided with insights into the mechanisms by which SPEG alterations could cause CNM and dilated cardiomyopathy (DCM)
Summary
Centronuclear myopathies (CNMs) are a group of congenital myopathies characterized by clinical features of muscle weakness, increased central nuclei, and genetic heterogeneity [1]. The primary amino acid sequence immediately upstream of the carboxy terminal kinase domain is significantly longer in SPEG compared with related proteins, effectively increasing the physical distance between the carboxy terminal kinase and the other functional domains This distance is highly conserved across species for each kinase, indicating that the spatial relationship between kinase domains is critical to their catalytic activities. Whereas consistent distances between Ig and FnIII domains indicate that SPEG and obscurin maintain highly conserved and potentially overlapping localization sites [25,37], distinct spatial properties of the dual kinase motifs suggest unique phosphorylation targets [25]. Sci. 2021, 22, 5732 whereas SPEG localizes in a double line of skeletal muscle, in alignment with the terminal cisternae of the SR and plays a critical role in maintaining triad structure and calcium handling [15]
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