Array profiling of dystrophin-deficient mice with a secondary glycosylation defect

A deletion in the CMAH gene in humans occurred approximately 3.5 million years ago. This resulted in the inactivation of the CMP-Neu5Ac hydroxylase enzyme, and hence, in the specific deficiency in N-glycolylneuraminic acid (Neu5Gc), a form of sialic acid, in all modern humans. Although there is evidence that this molecular milestone in the origin of humans may have led to the evolution of human-specific pathogens, how deficiency in Neu5Gc might alter progression of non-infectious human diseases remains unanswered. Here, we have investigated cardiac and skeletal muscle gene expression changes in mdx mice, a model of Duchenne muscular dystrophy (DMD), that do or do not carry the human-like inactivating mutation in the mouse Cmah gene. We have evidence that Neu5Gc-deficiency in humans might explain some of the discrepancies in the disease phenotype between mdx mice and DMD patients. The study had four groups of mice: 1) Wild type, 2) Cmah KO (mice carrying a human-like mutation in the Cmah gene and hence have human-like deficiency in Neu5Gc sialic acid), 3) mdx (mouse model for Duchenne Muscular Dystrophy), and 4) mdx mice deficient in Cmah. Gene expression was studied in heart and gastrocnemius muscle samples. Three replicates per group/tissue.人类CMAH基因（CMAH gene）上的一段缺失突变约发生于350万年前，该突变导致CMP-Neu5Ac羟化酶（CMP-Neu5Ac hydroxylase）失活，进而使所有现代人类体内均出现N-羟乙酰神经氨酸（Neu5Gc，一种唾液酸类物质）的特异性缺失。尽管有证据表明，这一人类起源过程中的分子里程碑或许推动了人特异性病原体的演化，但Neu5Gc缺失如何影响非感染性人类疾病的病程进展，目前仍未明确。本研究针对两类mdx小鼠（mdx mice，杜氏肌营养不良（Duchenne muscular dystrophy, DMD）模型）展开分析，探究其心脏与骨骼肌的基因表达变化：一类携带类人源小鼠Cmah基因失活突变，另一类则不携带该突变。研究发现，人类的Neu5Gc缺失或许可以解释mdx小鼠与DMD患者之间部分疾病表型的差异。本研究共设置四组小鼠：1）野生型小鼠；2）Cmah基因敲除（Cmah KO）小鼠（携带类人源Cmah基因突变，因此呈现类人Neu5Gc唾液酸缺失表型）；3）mdx小鼠（杜氏肌营养不良小鼠模型）；4）Cmah缺失的mdx小鼠。研究对心脏与腓肠肌（gastrocnemius muscle）样本开展基因表达分析，每组对应组织设置3个生物学重复。