Taniguchi Mariko, Kurahashi Hiroki, Noguchi Satoru, Sese Jun, Okinaga Takeshi, Tsukahara Toshifumi, Guicheney Pascale, Ozono Keiichi, Nishino Ichizo, Morishita Shinichi, Toda Tatsushi
Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Biochem Biophys Res Commun. 2006 Apr 7;342(2):489-502. doi: 10.1016/j.bbrc.2005.12.224. Epub 2006 Feb 3.
Fukuyama-type congenital muscular dystrophy (FCMD) and laminin-alpha2 deficient congenital muscular dystrophy (MDC1A) are congenital muscular dystrophies (CMDs) and they both are categorized into the same clinical entity of muscular dystrophy as Duchenne muscular dystrophy (DMD). All three disorders share a common etiologic defect in the dystrophin-glycoprotein complex, which connects muscle structural proteins with the extracellular basement membrane. To investigate the pathophysiology of these CMDs, we generated microarray gene expression profiles of skeletal muscle from patients in various clinical stages. Despite diverse pathological changes, the correlation coefficient of overall gene expression among these samples was considerably high. We performed a multi-dimensional statistical analysis, the Distillation, to extract determinant genes that distinguish CMD muscle from normal controls. Up-regulated genes were primarily extracellular matrix (ECM) components, whereas down-regulated genes included structural components of mature muscle. These observations reflect active interstitial fibrosis with less active regeneration of muscle cell components in the CMDs, characteristics that are clearly distinct from those of DMD. Although the severity of fibrosis varied among the specimens tested, ECM gene expression was consistently high without substantial changes through the clinical course. Further, in situ hybridization showed more prominent ECM gene expression on muscle cells than on interstitial tissue cells, suggesting that ECM components are induced by regeneration process rather than by 'dystrophy.' These data imply that the etiology of FCMD and MDC1A differs from that of the chronic phase of classical muscular dystrophy, and the major pathophysiologic change in CMDs might instead result from primary active fibrosis.
福山型先天性肌营养不良（FCMD）和层粘连蛋白α2缺陷型先天性肌营养不良（MDC1A）均为先天性肌营养不良（CMD），它们与杜氏肌营养不良（DMD）都被归类为同一临床实体的肌营养不良。这三种疾病在肌营养不良蛋白 - 糖蛋白复合物中存在共同的病因缺陷，该复合物将肌肉结构蛋白与细胞外基底膜相连。为了研究这些CMD的病理生理学，我们生成了处于不同临床阶段患者骨骼肌的微阵列基因表达谱。尽管存在不同的病理变化，但这些样本之间整体基因表达的相关系数相当高。我们进行了一种多维统计分析——蒸馏法，以提取区分CMD肌肉与正常对照的决定性基因。上调的基因主要是细胞外基质（ECM）成分，而下调的基因包括成熟肌肉的结构成分。这些观察结果反映了CMD中活跃的间质纤维化以及肌肉细胞成分再生活性较低的情况，这些特征与DMD明显不同。尽管在所测试的标本中纤维化的严重程度有所不同，但ECM基因表达一直很高，并且在整个临床过程中没有实质性变化。此外，原位杂交显示肌肉细胞上的ECM基因表达比间质组织细胞上更突出，这表明ECM成分是由再生过程而非“营养不良”诱导的。这些数据表明FCMD和MDC1A的病因与经典肌营养不良慢性期的病因不同，CMD的主要病理生理变化可能反而源于原发性活跃纤维化。
