Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Glycobiology. 2013 Jul;23(7):833-43. doi: 10.1093/glycob/cwt020. Epub 2013 Mar 20.
Roughly 3 million years ago, an inactivating deletion occurred in CMAH, the human gene encoding CMP-Neu5Ac (cytidine-5'-monophospho-N-acetylneuraminic acid) hydroxylase (Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A. 1998. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci USA. 95:11751-11756). This inactivating deletion is now homozygous in all humans, causing the loss of N-glycolylneuraminic acid (Neu5Gc) biosynthesis in all human cells and tissues. The CMAH enzyme is active in other mammals, including mice, where Neu5Gc is an abundant form of sialic acid on cellular membranes, including those in cardiac and skeletal muscle. We recently demonstrated that the deletion of mouse Cmah worsened the severity of pathophysiology measures related to muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy (Chandrasekharan K, Yoon JH, Xu Y, deVries S, Camboni M, Janssen PM, Varki A, Martin PT. 2010. A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci Transl Med. 2:42-54). Here, we demonstrate similar changes in cardiac and skeletal muscle pathology and physiology resulting from Cmah deletion in α-sarcoglycan-deficient (Sgca(-/-)) mice, a model for limb girdle muscular dystrophy 2D. These experiments demonstrate that loss of mouse Cmah can worsen disease severity in more than one form of muscular dystrophy and suggest that Cmah may be a general genetic modifier of muscle disease.
大约 300 万年前，CMAH 基因（编码 CMP-Neu5Ac（胞苷-5'-单磷酸-N-乙酰神经氨酸）羟化酶）发生了一个失活缺失，这是人类基因。该缺失突变发生在人类与黑猩猩分化之后（Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A. 1998. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci USA. 95:11751-11756）。这个失活缺失现在在所有人类中都是纯合的，导致所有人类细胞和组织中 N-羟乙酰神经氨酸（Neu5Gc）的生物合成丢失。CMAH 酶在其他哺乳动物中是有活性的，包括老鼠，在老鼠中，Neu5Gc 是细胞膜上丰富的唾液酸形式，包括心脏和骨骼肌细胞膜上。我们最近证明，删除小鼠的 Cmah 会加重 mdx 小鼠（杜氏肌营养不良症的模型）肌肉病理生理学指标的严重程度（Chandrasekharan K, Yoon JH, Xu Y, deVries S, Camboni M, Janssen PM, Varki A, Martin PT. 2010. A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci Transl Med. 2:42-54）。在这里，我们证明了在α-横纹肌聚糖缺失（Sgca(-/-)）小鼠（肢带型肌营养不良 2D 的模型）中 Cmah 缺失导致的心脏和骨骼肌病理和生理学的相似变化。这些实验表明，小鼠 Cmah 的缺失可以使多种形式的肌营养不良症的严重程度恶化，并表明 Cmah 可能是肌肉疾病的一般遗传修饰因子。
