Duchennes muscular dystrophy is an X-linked neuromuscular disease that manifests as
Duchennes muscular dystrophy is an X-linked neuromuscular disease that manifests as muscle atrophy and cardiomyopathy in young boys. of the X chromosome and approximately 0.1% of the entire human genome [4,16,17,18]. A majority of the gene sequence (99%) consists of introns, while the coding sequence is divided into 79 constitutive exons. The full-length messenger RNA is 14,000 base pairs (bp) long and is transcribed from three different promoters: the upstream brain (B), muscular (M) and purkinje (P) promoters drive the transcription of three full-length isoforms (Dp427) that have the same number of exons but are expressed in a tissue-specific manner  reflected in the name assigned to each promoter that refers to the principal tissue expression site. In particular, purchase S/GSK1349572 the B promoter guides the expression of dystrophin mainly in hippocampal and cortical neurons [19,20] while the P promoter is active in cerebellar Purkinje cells [21,22]. Lastly, the M promoter is utilized to express dystrophin in skeletal and cardiac myocytes  and at very low levels in glial cells . In addition to these full-length mRNAs, gives rise to another four different transcripts each starting from a specific promoter. These promoters are located in the gene body; within intron 29 (R, retinal isoform, Dp260), intron 44 (B3, brain-specific isoform, Dp140), intron 55 (S, Schwann cell isoform, Dp116), and intron 62 (G, general isoform, Dp71) purchase S/GSK1349572 [4,25]. has homology with other different gene classes. In particular, the whole coding sequence shows high similarity with the utrophin gene : the 5 end and central parts have homology with proteins of the spectrin family (e.g., -actinin) while the 3 end is homologous to dystrobrevin (a post-synaptic protein) . In addition to these isoforms, alternative Rabbit Polyclonal to Akt (phospho-Thr308) splicing of produces other different isoforms that are tissue-specific, increases the diversity of the dystrophin protein, and explains the complexity of expression regulation for tissue-specific functions. purchase S/GSK1349572 3.2. The Dystrophin Protein The full-length dystrophin protein (that arises from the B, M, or P promoters) is a large rod-shaped protein containing about 3685 amino acids with a molecular weight of 427kDa. This large protein folds into four different protein domains: the amino-terminal domain, the central rod-like domain, the cysteine-rich domain, and the C-terminal domain [4,25]. The amino-terminal region, encoded by exons 1C8, shows high homology having a grouped category of actin-binding proteins, in particular, -spectrin and -actinin . This site is definitely the primary area of interaction using the actin cytoskeleton since three actin-binding sites have already been within this section. Nevertheless, additional downstream sites have already been identified that effect dystrophin-actin relationships . The rod-like site may be the largest area of the proteins and it is encoded by exons 9C63 . It includes 24 devices with high homology towards the repeated areas in the -spectrin proteins and is expected to create triple helical coiled coils . Four brief proline-rich spacers, the so-called hinge domains offering elasticity towards the proteins , interrupt this area. The rod site also contains another actin-binding theme  and interacts with anionic lipids , neuronal NOS (nNOS) [34,35], and polarity regulating kinase (PAR-1b). The cysteine-rich site can be encoded by exons 64C69 possesses two EF-hand-like modules that are destined by WW and ZZ domains [36,37] which are essential for proteinCprotein discussion as well as for the stabilization of dystroglycan binding . The C-terminal area, encoded by exons 70C79 , can be fundamental for the binding with several extracellular (-dystroglycan),.