The rod domain is the central domain of the protein which represents about 75% of the dystrophin. This domain is composed of 24 repeats (R1 to R24) homologue to spectrin repeats and 4 hinges (H1 to H4) [Koenig et al., 1989,, Winder et al., 1995] These hinges share the rod domain into three sub-domains. Repeats can be aligned according to a heptad motif and they may fold into three alpha-helices which constitute left-handed antiparallel triple-helical coiled coils. Today, no structure of dystrophin repeats is available, probably because of their high conformational flexibility.

The cysteine-rich domain contains a high number of cysteine residues and overlaps with the end of WW domain, the two EF hands and the zinc finger domain (ZZ). The WW domain is defined by the presence of two tryptophan residues which are spaced by 21 amino acids. This domain is followed by an alpha-helix and two EF-hand-like domains. An EF hand is a helix-loop-helix motif found in many calcium binding proteins. However, no calcium binding has yet been reported in dystrophin EF hands and it seems that dystrophin may have lost this property. All these domains have been crystallized and their tri-dimensional structure resolved by X-ray crystallography [Huang et al., 2000]. These domains are followed by a zinc finger domain. These four domains are involved in the binding of β-dystroglycan to dystrophin (see here).

The COOH Terminus consists of two polypeptides which form a coiled-coil with a conserved repeated heptad pattern of the residues similar to the rod domain repeats.

Dystrophin is a skeletal-muscle protein that confers resistance to the sarcolemma against the stress of contraction-relaxation cycles by connecting various cytoskeletal elements such as actin and micro-tubules to the intrinsic protein, β dystroglycan.

K19 - Keratin binding: Dystrophin can bind Keratin 8 and 19 through the two CH domains and associates preferentially with K19 [Stone et al., 2005].

ABD1 & ABD2 - Actin binding property: The two CH domains in tandem constitute the Actin-Binding Site 1 of dystrophin [Banuelos et. al, 1998, Norwood et. al, 2000]. CH1 has a strong affinity to actin whereas CH2 enhances the binding affinity but alone does not bind to F-actin. Interaction with F-actin is localized in the hydophobic groove identified on the surface of CH1 which extends into the CH2.
The second Actin-Binding Domain encompasses the repeats R11 to R17 and interacts with F-actin through an electrostatic interaction [Amann et al, 1999]. It does not display any binding activity on G-actin.

LBD1 & LBD2 - Lipid binding property: Part of the rod domain of dystrophin is a partner of anionic membrane phospholipids [Legardinier et al., 2008 and Vié et al., 2010]. The functional domain is divided into two parts: one lipid binding domain (LBD1) comprises the repeats R1 to R3 whereas a second lipid binding domain (LBD2) comprises repeats R4 to R19. This interaction places dystrophin very near the sarcolemma with a large part of the central rod domain lying along the phospholipid membrane bilayer.

PAR-1b binding domain: PAR-1b is a cell polarity kinase. Recent reports have revealed interactions between repeats 8 and 9 of dystrophin and utrophin with Par-1b kinase. In both cases the kinase appears to phosphorylate the repeats [Yamashita et al., 2009].

Synemin binding: Dystrophin can bind intermediate filaments through a direct binding with synemin, one of the proteins of the intermediate filaments [Bhosle et al., 2006]. A first synemin binding domain is localized on the rod domain, more specifically on repeats R11 to R14, which overlaps with the ABD2. A second binding domain encompasses the WW to ZZ domain.

nNOS binding: Sarcolemma-associated neuronal NOS plays a key role in muscle physiology. nNOS can bind R16-17 of the dystrophin rod domain [Lai et al., 2009].

Plectin binding property Plectin, a large cytolinker protein that can connect actin filaments, intermediate filaments and microtubules, has also been shown to make interactions with dystrophin with the cys-rich domain, therefore providing an indirect link with the intermediate filament protein desmin [Rezniczek et al., 2007].

βDG - β-Dystroglycan binding Dystrophin interacts with β-Dystroglycan through the WW domain, the two EF hands, and the ZZ domain. A structure of β-DG together with the dystrophin WW, EFH1 & EFH2 has been resolved by X-ray crystallization by Huang et al., 2000. Thereafter, Hnia et al., 2007 and Ishikawa et al., 2004 showed that β-DG has only a reduced binding activity with the WW and EF hands of dystrophin and that the addition of the ZZ domains restored a high binding activity of β-DG to dystrophin.

Syntrophin and Dystrobrevin binding These proteins are two dystrophin-related proteins whose C-termini are similar to the C terminus homologous with the C terminus of dystrophin. Both are able to combine with the first helix of the dystrophin coiled-coil C terminus motif [Sadoulet et al., 1997, Newey et al., 2000].

Myospryn binding Myospryn is a muscle-specific protein kinase A (PKA) anchoring protein or AKAP. Myospryn interacts with dystrophin through the WW domain, the two EF hands, and the ZZ domain [Reynolds et al., 2008].

Ankyrin binding Ankyrins are a family of adaptators proteins. Dystrophins binds ankyrin-B and ankyrin-G while βDG biends ankyrin-G. Ankyrin-dependent organization of sarcolemmal dystrophin and βDG is required for sarcolemmal integrity during physical exercise [Ayalon et al., 2008].

Dystrophin plays a key role in organizing muscle function into contraction-relaxation cycles. A deficiency of dystrophin disrupts the muscle membrane, alters calcium channel activity and finally, leads to apoptosis and necrosis of muscle cells [Batchelor and Winder, 2006, Blake et al., 2002].

Mutations in the DMD gene can lead to two major diseases: Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD). In most of cases, DMD results from a frame shift mutation which leads to mRNA decay and a total absence of dystrophin in muscle cells. On the other hand, BMD results from an in-frame mutation which leads to an internally truncated dystrophin that is threfore only partially functional. This rule was established by [Monaco et al., 1988] but there are some exceptions.

Duchenne Muscular Dystrophy (DMD) is an X-linked disease with an incidence of around 1:3,500 male births. Patients are usually confined to a wheelchair before the age of 12 and have a life span reduced to about 20 years. No dystrophin is observed in the muscle cells of these patients.

Becker Muscular Dystrophy (BMD) is a less severe X-linked disease leading to highly variable phenotypes from patients with only weakness to patients confined to a wheelchair. An internally truncated dystrophin is observed in muscle cells with very usually a decrease in the protein level compared with normal humans. As the dystrophy is less severe as a whole compared with DMD, it appears that these mutated dystrophins remain partially functional and able to somewhat compensate for the function of full length dystrophin.

Intermediate Muscular Dystrophy (IMD) can be observed in some patients. These patients have an intermediate phenotype and are confined to a wheelchair between the ages of 13 to 16.

X-linked cardiomyopathy is an isolated cardiomopathy. These patients have no skeletal-muscle disorders.

Injection of DMD gene is the initial approach for gene therapy strategy to envisage. A truncated gene is encapsuled in a recombinant adeno-associated virus and injected into patients [Gregorevic et al., 2006]. Then, a functional truncated dystrophin is produced by the patient's cells. The size of the delivered gene is limited by the vector size and therefore reduced DMD genes (mini- or micro-gene) have been constructed to be encapsulated in recombinant adeno-associated viruses. These mini- or micro-genes may be able to produce partially functional internally truncated dystrophins such as those observed in BMD.

Exon skipping therapy is one of the most promising experimental therapies for Duchenne Muscular Dystrophy [Beroud et al., 2007], [Arnett et al., 2009]. This skipping restores a true reading frame leading to the synthesis of a dystrophin deleted for part of the central coiled-coil region as observed in BMD patients. This strategy should transform a DMD patient into a BMD patient [Goyenvalle et al., 2004, Aartsma-Rus et al., 2002]. Antisense oligonucleotides (AO) are used to alter gene expression by skipping one or more exons in the final transcript with different associated strategies [Wilton & Fletcher, 2008, Goyenvalle et al., 2010].
However, this strategy has some limitations. AOs can be used to skip all single exons except the first and last exons. The exon skipping strategy is mutation-specific but some exon skipping strategies could be applicable to large groups of patients [Aartsma-Rus et al., 2009]. The mode of administration is not yet well defined to restore dystrophin expression particularly in cardiac muscle.

Cell therapy is an alternative therapy with the aim of restoring a pool of normal muscle cells in the skeletal or heart muscles. First, a transplantation of adult myoblasts is performed but these cells have only a limited survival time. Now, dissemination of skeletal muscle precursors being studied.