Project 462458

Centronuclear myopathy (CNM) is a childhood muscle disease associated with significant disabilities, including respirator and wheelchair dependence, and early mortality. CNMs are defined by characteristic muscle biopsy features, and a diagnosis of CNM is definitively established by finding a mutation in one of 5 genes associated with the disease. At present, there are no therapies for CNM, and the goal of my lab is to develop treatments for this devastating disease. One of the major barriers to developing therapy for CNM is an incomplete understanding of the disease process. Our group has identified abnormalities in a process called excitation contraction coupling (ECC) as a key driver of muscle weakness, but the link between the genes involved in CNM and ECC is still largely unknown. An important recent finding is the identification of recessive mutations in SPEG in patients with a severe form of CNM. This finding represents a great opportunity to bridge the gap in the understanding of CNM because SPEG is a special type of protein called a protein kinase. Protein kinases act to directly modify other proteins to change aspects of their structure and function. This property of SPEG, in combination with its large, repetitive structure, positions it as a key link between CNM disease genes and the muscle structures that are impacted in CNM patients. In this proposal, we will study the role of SPEG in muscle development, and define the direct consequences of SPEG mutations in terms of muscle pathology. To accomplish this, we will identify the proteins in muscle that SPEG interacts with and modifies, determine the impact of these associations on muscle development, and examine the changes in muscle caused by SPEG mutations. We will also perform a large scale drug screen to identify therapeutic candidates. Successful completion of the proposal will advance the understanding of CNM and of normal muscle development, and lead to new potential therapies.