Congenital myopathies (CM) are a heterogeneous group of skeletal muscle disorders that manifest as hypotonia as well as breathing and feeding difficulties early in life, and can often be fatal. Centronuclear myopathy (CNM) is a common CM subtype characterized by the mislocalization of nuclei from the periphery to the center of myofibers. X-linked myotubular myopathy, the most frequent and severe form of CNM, is caused by MTM1 mutations. Myotubularin or MTM1 is a lipid phosphatase, and little is known about its interacting partners. To determine MTM1-interacting proteins, we conducted a yeast two-hybrid screen and found striated preferentially expressed gene (SPEG) to be an interacting partner. Concurrently, whole exome sequencing to determine genetic basis of CNM revealed recessive SPEG mutations in probands from three unrelated CNM families. Two of the three were also diagnosed with dilated cardiomyopathy (DCM), one of which had spontaneous resolution by a year. Our results suggest that mutations in SPEG cause a CNM phenotype, but the underlying basis for skeletal muscle dysfunction is unknown. Knocking out Speg in a mouse model has been associated with severe DCM, an increased number of central nuclei, and death by postnatal day two. SPEG and desmin genes are tandemly arrayed on the genome, and a common locus control region in mammals regulates their expression. Immunofluorescence studies have shown that SPEG localizes with the terminal cisternae of the sarcoplasmic reticulum (SR). We propose that SPEG may maintain terminal SR structure for efficient excitation-contraction coupling.
In Aim 1, we will decipher the molecular mechanisms responsible for poor skeletal muscle function associated with lack of SPEG and its differential role in skeletal and cardiac muscles.
In Aim 2, we will investigate SPEG's involvement in skeletal muscle growth and differentiation, with special focus on central nucleation.
In Aim 3, we will determine the relationship between SPEG, MTM1, and desmin. The overall goals of the proposal are to understand how lack of SPEG affects muscle function, its role in muscle growth and differentiation, and relationship with MTM1 and desmin. When completed, this work will provide clear insights into the molecular functions of SPEG in skeletal muscle, and how its deficiency causes CNM. The findings will help determine therapeutic approaches against such devastating muscle diseases.
Congenital myopathies (CM) are genetic disorders of muscle that may affect normal ambulation, feeding and breathing. They are poorly understood with no available cures. We have identified SPEG protein deficiency in a few CM patients. The function of this protein is unknown, and we propose to determine disease mechanisms using cell and mouse models. This will help us better understand CM and devise appropriate future therapies.
Showing the most recent 10 out of 23 publications
