Mechanism of Disease-Causing Missense Mutations in Dystrophin
2009-04-08
Loading...
View/Download File
Persistent link to this item
Statistics
View StatisticsJournal Title
Journal ISSN
Volume Title
Title
Mechanism of Disease-Causing Missense Mutations in Dystrophin
Authors
Published Date
2009-04-08
Publisher
Type
Presentation
Abstract
Duchenne muscular dystrophy (DMD) is a fatal, x-linked disease that affects 1 in every 3,500 live born males. DMD is caused by the loss of the protein dystrophin due to genetic mutation. Dystrophin is abundant at the cell membrane of muscle cells, where its function is to stabilize the plasma membrane against contraction-induced membrane damage by binding to cytoskeletal f-actin filaments and the transmembrane protein dystroglycan. A small percentage of DMD cases are caused by missense mutations where the change in a single amino acid can cause severe disease. This disease can be caused by dystrophin not being able to bind its intracellular partners or by misfolding of the dystrophin protein, which can lead to degradation or insoluble aggregates. I investigated this aggregation as a possible mechanism for the pathogenesis of DMD missense mutations. I specifically worked with five missense mutations: K18N, L54R, L172H, Y231N, and T279A. These particular mutations are located in the actin-binding domain on the N-terminus of dystrophin. Of the fifteen known missense mutations in DMD patients, nine of them are found in this region. The missense mutations in this area can cause disease in one of two ways. The mutations can cause the protein to fold improperly, which leads to the aggregation and the loss of its localization to the membrane. The mutations can also render the protein unable to bind actin properly, despite normal folding and transportation of the protein to the membrane. For this project, I compared the levels of insoluble protein for various types of mutant dystrophin to the levels of wild type (WT) dystrophin (data provided by D.M. Henderson) to determine whether the mutations cause misfolding. I hypothesized that disease-causing missense mutations in the N-terminal actin binding domain of dystrophin cause misfolding and increase the level of insoluble dystrophin in vivo.
Description
Additional contributors: Davin M. Henderson; James Ervasti (faculty mentor).
Related to
Replaces
License
Series/Report Number
Funding information
This research was supported by the Undergraduate Research Opportunities Program (UROP).
Isbn identifier
Doi identifier
Previously Published Citation
Suggested citation
Lee, Ann. (2009). Mechanism of Disease-Causing Missense Mutations in Dystrophin. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/50749.
Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.