Expression profile of kidney from GNE M743T/M743T knock in mice and wild-type

Background. Mutations in GNE cause a recessive, adult onset myopathy characterized by slowly progressive distal and proximal muscle weakness. Knock-in mice carrying the most frequent mutation in GNE myopathy patients, GneM743T/M743T, usually die few days after birth from severe renal failure, with no muscle phenotype. However, a spontaneous sub-colony remains healthy throughout a normal lifespan without any kidney or muscle pathology. Objective. We attempted to decipher the molecular mechanisms behind these phenotypic differences and to determine the mechanisms preventing the kidney and muscles from disease. Methods. We analyzed the transcriptome and proteome of kidneys and muscles of sick and healthy GneM743T/M743T mice. Results. The sick GneM743T/M743T kidney was characterized by up-regulation of extra-cellular matrix degradation related processes and by down-regulation of oxidative phosphorylation and respiratory electron chain pathway, that was also observed in the asymptomatic muscles. Surprisingly, the healthy kidneys of the GneM743T/M743T mice were characterized by up-regulation of hallmark muscle genes. In addition he asymptomatic muscles of the sick GneM743T/M743T mice showed upregulation of transcription and translation processes Conclusions. Overexpression of muscle physiology genes in healthy GneM743T/M743T mice seems to define the protecting mechanism in these mice. Furthermore, the strong involvement of muscle related genes in kidney may bridge the apparent phenotypic gap between GNE myopathy and the knock-in GneM743T/M743T mouse model and provide new directions in the study of GNE function in health and disease. Overall design: Four male mice up to 3 months, of each state (sick, healthy-mutated or wild-type)

研究背景：GNE突变可导致一种常染色体隐性遗传的成人起病型肌病（GNE myopathy），临床特征为缓慢进展的远端与近端肌肉无力。携带该肌病患者中最常见突变的敲入小鼠（knock-in mice）GneM743T/M743T，通常在出生后数日内因严重肾衰竭死亡，且无肌肉表型。但其中一个自发形成的亚群小鼠可维持正常寿命，全程无肾脏或肌肉病理改变。
研究目的：本研究旨在解析上述表型差异背后的分子机制，并阐明保护肾脏与肌肉免受疾病累及的潜在通路。
研究方法：我们对患病及健康GneM743T/M743T小鼠的肾脏与肌肉组织开展了转录组（transcriptome）与蛋白质组（proteome）分析。
研究结果：患病GneM743T/M743T小鼠的肾脏表现为细胞外基质降解相关通路的上调，以及氧化磷酸化与呼吸电子链通路的下调，这一特征同样见于无症状小鼠的肌肉组织中。令人意外的是，健康GneM743T/M743T小鼠的肾脏呈现标志性肌肉基因的上调表达。此外，患病GneM743T/M743T小鼠的无症状肌肉组织中，转录与翻译相关过程均出现上调。
研究结论：健康GneM743T/M743T小鼠中肌肉生理相关基因的过表达，似乎是其保护机制的核心特征。此外，肾脏组织中肌肉相关基因的显著富集，或可弥合GNE肌病与敲入小鼠模型GneM743T/M743T之间的表型差异鸿沟，同时为GNE在健康与疾病状态下的功能研究提供新方向。
实验整体设计：每组设置4只3月龄以内的雄性小鼠，分为患病组、突变健康组与野生型组。