Transcriptional profile in dermal fibroblasts from patients with collagen VI related muscular dystrophy

Objectives: The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies, but the pathogenesis, including the role of mutant collagen VI in the matrix is poorly understood. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD patients from controls.Methods: We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD patients (8 dominant negative and 5 null) and 6 controls. Sequence reads were analyzed using the TopHat/Cufflinks pipeline.Results: Differentially expressed transcripts between COL6-RD patient and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples

研究目的：VI型胶原相关肌营养不良（collagen VI related muscular dystrophies, COL6-RD）、Ullrich先天性肌营养不良（Ullrich congenital muscular dystrophy, UCMD）以及Bethlem肌病（Bethlem myopathy, BM）是最常见的先天性肌营养不良亚型之一，但目前对其发病机制，包括突变型VI型胶原在细胞外基质中的作用，仍缺乏深入认知。为更清晰地阐明VI型胶原突变所扰乱的生物学通路，本研究采用RNA测序（RNA-Seq）转录组分析手段，以鉴定COL6-RD患者与健康对照个体之间的差异表达基因。
研究方法：本研究对13例COL6-RD患者（8例携带显性负效突变，5例为无效突变）及6例健康对照者的培养皮肤成纤维细胞开展RNA测序，以筛选差异表达基因。测序读段采用TopHat/Cufflinks分析流程进行生物信息学处理。
研究结果：COL6-RD患者与对照成纤维细胞间的差异表达转录本包括细胞外基质（ECM）组分的上调，以及调控基质重塑与修复的因子的下调。其中，显性负效突变组与无效突变组样本可通过无效突变样本中DNA复制与修复相关基因的下调实现区分。