Analysis of phenotype and genotype in a family with late infantile metachromatic leukodystrophy / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To study genotype-phenotype correlation of a family with late infantile metachromatic leukodystrophy(MLD).</p><p><b>METHODS</b>Clinical data were collected and ARSA gene was tested by PCR and sequencing in a pedigree.</p><p><b>RESULTS</b>The male proband onset with walking dysfunction at 19 months, arylsulfatase A activity of leucocyte from his peripheral blood was 20.2 nmol/mg.17h, and his cranial MRI showed wildly symmetrical demyelination. Homozygosis for novel c.622delC (p.His208Metfs46X) in exon 3 of ARSA gene was identified in proband, and heterozygous for the same mutation in parents and grandma of the proband.</p><p><b>CONCLUSION</b>Late infantile metachromatic leukodystrophy is characterized by rapid and progressive regression of neuropsychiatric and motor development. There is a significant correlation between the mutation of c.622delC(p.His208Metfs*46) in the ARSA gene and the phenotype presenting as O/O patients.</p>

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

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 confirmed:Calponin 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.

Mechanism of DMD with gene defect and change of protein structure / 中国病理生理杂志

AIM:To examine the relationship between the gene defect,change of protein hydrophobicity,spacial structure change and clinical phenotypes of Duchenne muscular dystrophy(DMD),and to explore the molecular pathogenesis of DMD.METHODS:The gene sequences of 59 cases of DMD/BMD patients with deletion from mutation were analyzed.The relationship between the protein hydrophobicity,3D-spacial structure and clinical phenotypes was examined by biological informatic technology.RESULTS:50 cases of frameshift mutation were all DMD.In other 5 cases with codon mutation that involved the 3rd hydrophobic region,4 cases were diagnosed as DMD and the rest one was BMD.The exon 3 deletion leaded to the intortion of dystrophin N-terminal,which in turn affected the combination of dystrophin and troponin resulting in the DMD pathopoiesis.CONCLUSION:The severity of clinical phenotypes of muscular dystrophy diseases is related to whether the deletion destroys the reading frame,involves the 3rd hydrophobic region or changes the protein special structure.The biological informatic technology provides a new potential research methodology for studying the pathogenesis of DMD.