Effects of the dystrophin hydrophobic regions in the pathogenesis of Duchenne muscular dystrophy A three-dimensional reconstruction verification / 中国组织工程研究

ABSTRACT

BACKGROUND:Duchenne muscular dystrophy is recognized as a fatal X-linked recessive inheritance. It is caused by the dystrophin gene mutation, resulting in the deficiency of dystrophin and consequent degeneration and necrosis of muscle fibers gradual y. Becker muscular dystrophy is also caused by the mutation of the same gene, but presented with less severe clinical symptoms compared with Duchenne muscular dystrophy. Frameshift mutation destroys the reading frames, and thus the translation cannot proceed smoothly to transcript functional proteins. In-frame mutation cannot destroy the reading frames and hence the translation can proceed smoothly. But in-frame mutation involves the whole hydrophobic regions. The three-dimensional structure of these regions and their functionality are not interpreted clearly. The effects of these regions on disease development need to be clarified in detail from the point of structure and function. OBJECTIVE:By analyzing Kate and Dolittle scale mean hydrophobicity profile, to investigate the dystrophin hydrophobic regions using Swiss-model so as to provide the supplement explanation on the reading frame rule. METHODS:Form 2002 to 2013, 1 038 cases diagnosed as Duchenne muscular dystrophy or Becker muscular dystrophy were col ected in the First Hospital of Sun Yat-sen University in China and Leiden DMD information database was searched with deletion of codon mutation information available. The correlation between clinical types and genotypes was analyzed upon resources col ected above. The mean hydrophobicity profile of dystrophin was analyzed by Bioedit as wel as the reconstruction of hydrophobic domains using Swiss-model. Thus, the important functional domain of dystrophin was confirmed by analysis and the correlation between clinical types and genotypes. RESULTS AND CONCLUSION:Four hydrophobic regions were confirmedCalponin homology domain CH2 on actin-binding domain, repeat 16 domain, Hinge Ⅲ domain and EF Hand domain. Duchenne muscular dystrophy was developed as a result of the destruction of the 1st, 2nd and 4th hydrophobic regions which were the conjunction of dystrophin and associated protein in dystrophin-glycoprotein complex. When the 3rd hydrophobic was deleted, the repeat domain located on central rob domain remained its continuity so that the clinical symptoms were less severe. These findings indicate that the dystrophin hydrophobic regions act as an important role on the pathogenesis of Duchenne muscular dystrophy.