期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 27, 期 12, 页码 4340-4346出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00379-07
关键词
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资金
- NHLBI NIH HHS [HL057345, P01 HL057345] Funding Source: Medline
- NIDCD NIH HHS [DC00139, R01 DC000139] Funding Source: Medline
- NIGMS NIH HHS [R37 GM032373, GM32373, R01 GM032373] Funding Source: Medline
- BLRD VA [I01 BX001205] Funding Source: Medline
Humans and chimpanzees share > 99% identity in most proteins. One rare difference is a human-specific inactivating deletion in the CMAH gene, which determines biosynthesis of the sialic acid N-glycolylneuraminic acid (Neu5Gc). Since Neu5Gc is prominent on most chimpanzee cell surfaces, this mutation could have affected multiple systems. However, Neu5Gc is found in human cancers and fetuses and in trace amounts in normal human tissues, suggesting an alternate biosynthetic pathway. We inactivated the mouse Cmah gene and studied the in vivo consequences. There was no evidence for an alternate pathway in normal, fetal, or malignant tissue. Rather, null fetuses accumulated Neu5Gc from heterozygous mothers and dietary Neu5Gc was incorporated into oncogene-induced tumors. As with humans, there were accumulation of the precursor N-acetylneuraminic acid and increases in sialic acid 0 acetylation. Null mice showed other abnormalities reminiscent of the human condition. Adult mice showed a diminished acoustic startle response and required higher acoustic stimuli to increase responses above the baseline level. In this regard, histological abnormalities of the inner ear occurred in older mice, which had impaired hearing. Adult animals also showed delayed skin wound healing. Loss of Neu5Gc in hominid ancestors similar to 2 to 3 million years ago likely had immediate and long-term consequences for human biology.
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