Structure of the Dystrophine Gene
The dystrophin gene, located on the short arm of the X chromosom at locus p21, is one of the largest genes (2.4 Mb) in the human genome characterized to date, with 79 coding exons and seven tissue-specific promoters for seven protein isoforms.
Three promoters produce full-length messenger RNA (mRNA) transcripts (~ 14 kb) whose 427 kDa proteins differ only in their amino-terminal sequences.
These isoforms are brain (B); muscle (M), expressed in both skeletal and cardiac muscle; and Purkinje (P), expressed in both cerebellar Purkinje cells and skeletal muscle (Blake et al., 2002).
Besides a full-length gene transcription product, the dystrophin gene also has at least four internal promoters, which give rise to shorter dystrophin transcripts that encode truncated C-terminal isoforms.
These isoforms are primarily expressed in nonmuscle tissues, including the brain, central and peripheral nervous system tissues, and lung, and are thought to provide the necessary binding sites for a number of dystrophin-associated proteins (Schofiedl et al., 1994). However, the molecular and cellular function of these isoforms has not been elucidated.
Mutations Opens in new window in the dystrophin gene can be classified into two main categories according to the size of the deletion: large and small.
The vast majority of large deletions are clustered around two mutation hot spots, which result in loss of part of the rod domain or the actin-binding domain of the protein, or both (Kunkel et al., 1989).
The rod domain can have large in-frame deletions without serious clinical consequences, which has facilitated the design of dystrophin mini-genes for gene therapy approaches.
Approximately two thirds (70%) of boys with Duchenne muscular dystrophy (DMD) Opens in new window have large deletions or duplications in the dystrophin gene and the other third (30%) have smaller insertion or deletion mutations, splice mutations, or other small point mutations.
Deletions may occur at any point along the dystrophin gene, with most occurring in two hot spots within the gene (Mendell, Buzin, Feng, et al., 2001).
These deletions or mutations Opens in new window disrupt essential functional domains of the dystrophin molecule, resulting in a truncated and unstable dystrophin protein with impaired function.
In muscles, dystrophin Opens in new window is part of a protein complex. Dystophin deficient muscle fibers are susceptible to contraction-induced tears that allow calcium influx and ultimately lead to muscle fiber necrosis.
Muscle fiber regeneration can only partially compensate so that fibers are progressively replaced by fat and connective tissue.
The dystrophin protein Opens in new window is nearly absent in the muscles of boys with Duchenne muscular dystrophy (DMD) Opens in new window (Hoffman & Wang, 1993) and partially absent in Becker muscular dystrophy Opens in new window (BMD), a milder form of muscular dystrophy Opens in new window.
The gene also codes for protein products that localize to other tissue types, including the brain, and the absence of these products is associated with cognitive dysfunction (Felisari, Martinelli-Boneschi, Bardoni, et al., 2000).
- Pagon, R. A., Hanson, N.B., Neufeld-Kaiser, W., et al. (2001). Genetic consultation. West J Med, 174(6), 397-399.
- Williams, O. (2007). Diseases of muscle. In Brust, J.M.C. (Ed.), Current Diagnosis and Treatment in Neurology. New York: McGraw-Hill.
- Muntoni, F., Torelli, S., & Ferlini, A. (2003). Dystrophin and mutations: One gene, several proteins, multiple phenotypes. Lancet Neurology, 2, 731-740.
- Do, T. (2002). Orthopedic management of the muscular dystrophies. Curr Opin Pediatr, 14, 50-53.
- McClorey, G., Moulton, H.M., Iversen, P.L., et al. (2006). Antisense oligonucleotide-induced exon skipping restores dystrophin expression in vitro in a canine model of DMD. Gene Ther, 13(19), 13373-1381.