Hereditary neuropathies of the Charcot-Marie-Tooth (CMT) type comprise the most common inherited neurological disorders and are genetically heterogeneous. The principal investigator and 1 co-investigator on this application have recently identified the mitochondrial fusion factor Mitofusin 2 (MFN2) as a cause for CMT type 2A (CMT2A), the most frequent (=20%) axonal form of hereditary peripheral neuropathies. MFN2 plays a significant role in maintaining the fusion/fission balance for mitochondria. However, how MFN2 mutations lead to a human disease is unknown. In MFN2 knock-out mice the -/- mice died in utero, while the mice showed no signs of neuromuscular disease. These results may indicate loss of function effect for this autosomal dominant disorder. In the light of the success of the PMP22 mouse for demyelinating neuropathies, we think it is important but apparently not easy, to have a mouse model available for future studies of axonal neuropathies. This application aims to combine human genetics with cell biology in order to develop a transgenic mouse model mimicking the human disease. Such a mouse model, based on mutations found in CMT patients, could potentially gain high importance for several reasons: 1) The pathophysiology of MFN2 dysfunction in relation to neuropathies is unknown, although involvement of mitochondrial dysfunction in neuromuscular diseases is well recognized., 2) Axonal neuropathies in general are more frequent then demyelinating forms, but a mouse model for the most common CMT2 form, CMT2A, is missing. 3) There is no treatment available for axonal CMT patients, but recent studies based on mouse models for demyelinating neuropathies revealed for the first time promising results for future treatment. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052767-03
Application #
7492100
Study Section
Special Emphasis Panel (ZRG1-NDBG-A (09))
Program Officer
Porter, John D
Project Start
2006-04-17
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$334,267
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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