Congenital Myopathies
Congenital Myopathies are a clinically and genetically heterogeneous group of conditions that most commonly present at or around the time of birth with hypotonia, muscle weakness, and (often) respiratory distress. The Agrawal Laboratory has identified several genes including striated preferentially expressed gene (SPEG), cofilin-2 (CFL2) and titin (TTN) to be mutated in those conditions. I have utilized various models including zebrafish and mouse models to determine the pathogenicity of those mutations and determine potential therapeutic approaches.
SPEG
We have identified three unrelated centronuclear myopathy (CNM)-affected probands, including two with documented dilated cardiomyopathy, carrying homozygous or compound-heterozygous SPEG mutations. Examination of muscle samples from Speg-knockout mice revealed an increased frequency of central nuclei, as seen in human subjects. SPEG localizes in a double line, flanking desmin over the Z lines, and is apparently in alignment with the terminal cisternae of the sarcoplasmic reticulum. Examination of human and murine MTM1-deficient muscles revealed similar abnormalities in staining patterns for both desmin and SPEG. Our results suggest that mutations in SPEG, encoding SPEG, cause a CNM phenotype as a result of its interaction with MTM1. SPEG is present in cardiac muscle, where it plays a critical role; therefore, individuals with SPEG mutations additionally present with dilated cardiomyopathy.
Related Publications:
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Dynamin-2 reduction rescues the skeletal myopathy of SPEG-deficient mouse model
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Striated Preferentially Expressed Protein Kinase (SPEG) in Muscle Development, Function, and Disease
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Homozygous SPEG Mutation Is Associated With Isolated Dilated Cardiomyopathy
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SPEG binds with desmin and its deficiency causes defects in triad and focal adhesion proteins
Cofilin-2 (the actin-binding protein muscle cofilin-2)
We have reported the identification of a sixth nemaline myopathy (NM) gene, CFL2, encoding the actin-binding protein muscle cofilin-2, which is mutated in two siblings with congenital myopathy. The proband's muscle contained characteristic nemaline bodies, as well as occasional fibers with minicores, concentric laminated bodies, and areas of F-actin accumulation. Her affected sister's muscle was reported to exhibit nonspecific myopathic changes. Cofilin-2 levels were significantly lower in the proband's muscle, and the mutant protein was less soluble when expressed in Escherichia coli, suggesting that deficiency of cofilin-2 may result in reduced depolymerization of actin filaments, causing their accumulation in nemaline bodies, minicores, and, possibly, concentric laminated bodies.
Related Publications:
Additional Congenital Myopathies Discovered
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Actin
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TITIN
