Regulation Of Myotubularin Function By The Novel 3-phosphatase Adapter Protein (3-PAP)
Funder
National Health and Medical Research Council
Funding Amount
$488,273.00
Summary
Phospholipids are important components of cell membranes. Phospholipids are turned-on by enzymes called kinases and these phospholipids stimulate a variety of critical functions within the cells. Phospholipids are turned-off by another type of enzymes classed as phosphatases, thereby switching off a broad range of cell functions. Myotubularin is an enzyme, which neutralizes particular type of phospholipids that are involved in the shuttling of proteins between compartments within the cell. Loss ....Phospholipids are important components of cell membranes. Phospholipids are turned-on by enzymes called kinases and these phospholipids stimulate a variety of critical functions within the cells. Phospholipids are turned-off by another type of enzymes classed as phosphatases, thereby switching off a broad range of cell functions. Myotubularin is an enzyme, which neutralizes particular type of phospholipids that are involved in the shuttling of proteins between compartments within the cell. Loss of function of myotubularin, due to inherited genetic changes (mutations), leads to abnormal muscle development manifesting as weakness since birth, and this particular disease is known as 'X-linked myotubular myopathy'. However, there is yet no information on the mechanisms by which failure of protein shuttling (transport) causes myopathy. We have discovered a new protein, 3-phosphatase adapter protein (3-PAP) that links with myotubularin and plays an important role in the function of myotubularin. Our research proposal seeks to clarify the important role of 3-PAP in the development of muscle cells. We propose to study the location of 3-PAP within cells and analyse the influence of 3-PAP on protein shuttling. We have created mice that are deficient in the 3-PAP gene. These special mice will help us understand the importance of 3-PAP in the development and function of nerve and muscle tissue.Read moreRead less
Novel Features And Mechanisms Of Congenital Myopathies
Funder
National Health and Medical Research Council
Funding Amount
$464,500.00
Summary
Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early childhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In addition, the congen ....Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early childhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In addition, the congenital myopathies have features in common with virtually all muscle diseases such as slow fibre predominance and alterations in contractile force. We are using nemaline myopathy as a representative congenital myopathy to examine features in common amongst the myopathies, characteristic of the congenital myopathies and specific to nemaline myopathy. In nemaline myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of the sarcomere. A feature specific to nemaline myopathy is the presence of abnormal structures of the sarcomere called nemaline rods. We have analysed a large number of nemaline myopathy patients that have mutations in the genes that encode the filament proteins alpha-skeletal actin and tropomyosin. In addition, we have generated mouse models for nemaline myopathy and propose to generate an additional one with novel features. Our mouse model has revealed that a feature previously thought exclusive to dystrophies, is also present in nemaline myopathy. The combined analysis of well-characterised patient samples and mouse models will allow us to address longstanding questions about this particular congenital myopathy and myopathies in general. We will determine how rods form and their protein composition. Our mouse models in particular will allow us to address the molecular mechanisms that underpin the increase in slow twitch fibres and the effects that a particular mutation has on muscle function.Read moreRead less