The long-term goals of this project are to understand the role of Cofilin-2 (CFL2) in skeletal muscle and its mutation in congenital myopathies (CMs). CMs are characterized by relatively non-progressive skeletal muscle weakness, hypotonia presenting in early life. Nemaline Myopathy (NM), the most common type, is a genetic disorder with nemaline bodies present in the muscle and mutations identified in five different genes that constitute the thin filament. In a recent breakthrough, I have identified a sixth gene, CFL2, mutated in NM. Two siblings with clinical diagnosis of typical NM and non-specific congenital myopathy born to consanguineous parents carry a homozygous missense mutation c.103G>A (A35T), and exhibit drastically reduced levels of cofilin-2 protein in their muscles. In contrast, the amount of CFL2 mRNA is increased about 8 fold compared to normal controls. Cofilin-2 belongs to AC group of proteins that include cofilin-1, cofilin-2 and actin depolymerization factor. These proteins function by causing actin severance and depolymerization, and are essential in a wide range of cellular functions including locomotion, cytokinesis, endocytosis, and muscle development. This is the first identified case of a human mutation in the AC group of genes. The molecular mechanism of NM/congenital myopathy caused by this mutation needs to be understood. In addition, cofilin-2 function in skeletal muscle needs to be elucidated.
In Aim 1, we will screen all NM/other CM cases for CFL2 mutations and characterize the transcriptional profile associated with these mutations to understand downstream effects.
In Aim 2, we will evaluate the biochemical and functional consequences of the identified mutation.
In Aim 3, CFL2 expression in C2C12 cells will be knocked down using shRNA techniques and functional consequences will be evaluated.
In Aim 4, conventional Cfl2 knockout and c.103G>A mutation knockin mouse models will be generated. This project will introduce me to a variety of techniques including microarray analysis, gene-silencing and creating knockout/knockin mouse models. It willl give me the opportunity to work in an intellectually stimulating environment, where I will approach scientific questions in novel ways fostering my transition to independence. My sponsor Dr Beggs, collaborators/advisors Dr Darras, Dr Dormitzer, Dr Kohane, Dr Kunkel and Dr Maciver, and my Neonatology Division Chief Dr Kourembanas will help me in this process.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Boyce, Amanda T
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Children's Hospital Boston
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Subramanian, Khaushik; Gianni, Davide; Balla, Cristina et al. (2015) Cofilin-2 phosphorylation and sequestration in myocardial aggregates: novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy. J Am Coll Cardiol 65:1199-1214
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