DMD and Associated Diseases
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Backgrounds of DMD Gene
The DMD gene is the longest in humans, with 2.4 Megabases of DNA, accounting for about 1% of the X-chromosome DNA. It is localized on the locus p21 of chromosome X and codes for the protein dystrophin (Dp427m) in addition to two other full-length isoforms from the promoters Dp427c and Dp427p. The size of this gene is 2.2 Mb, and a large number of isoforms are expressed from seven different promoters and by alternative splicing in muscle and nonmuscle tissues. In the DMD gene, exons 45 to 55 are considered to be the hotspot region of mutations. This mutation results in a deficiency of protein dystrophin.
Fig.1 Domain Structure of Dystrophin. (Chamberlain, 2017)
Mutations of DMD Gene
Mutations in the dystrophin DMD gene are the cause of two devastating and so far incurable diseases, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). In the case of out-of-frame mutations, dystrophin is mostly deficient, which leads to severe DMD disease. In the case of in-frame mutations, the dystrophin would be expressed as a mutant protein, either a substitution of missense or a deletion or duplication of an internal part of the protein. Most of these in-frame mutations cause less severe BMD disorders.
Mechanisms/Pathophysiology
- DMD and dystrophin
DMD is caused by structural and/or functional defects in sarcolemma proteins resulting from mutations in the coding gene. Dystrophin and DMD are the pathogenic proteins and genes, respectively.
- Dystrophin-associated protein complex
Dystrophin and its binding partners form the dystrophin-associated protein complex (DAPC).
- Consequences of dystrophin deficiency
Dystrophin deficiency leads to the disassembly of DAPC and loss of the interaction between F-actin and the extracellular matrix.
Gene Therapy for DMD
For nearly three decades, DMD has been a major target for gene therapy. Gene therapy using AAV vectors has broad prospects for treating DMD. Gene therapy for DMD aims to restore the missing dystrophin by providing a functional copy of the DMD or by repairing the DMD. Gene addition therapy uses a viral vector to deliver a cDNA copy of a functional DMD to the affected tissue.
Creative Biolabs is 100% committed to gene therapy development. Our team of highly qualified and experienced technicians will work with you to develop and deliver testing and analysis solutions that add value to your product or project. Our laboratory is flexible to meet the unique needs of our client's projects. We have the expertise to optimize each stage to ensure you get the results you want and achieve the highest level of efficiency. Please do not hesitate to contact us for your preferred solution or advice.
Reference
- Chamberlain, J.R.; Chamberlain, J.S. Progress toward gene therapy for Duchenne muscular dystrophy. Molecular Therapy. 2017, 25(5): 1125-1131.
