CHRFAM7A, a human-specific and partially duplicated α7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury

Conventional wisdom presumes that the a7nAChR product of CHRNA7 expression mediates the ability of the vagus nerve to regulate the inflammatory response to injury and infection. Yet, 15 years ago, a 2nd structurally distinct and human-specific a7nAChR gene was discovered that has largely escaped attention of the inflammation research community. The gene, originally called dupa7nAChR but now known as CHRFAM7A, has been studied exhaustively in psychiatric research because of its association with mental illness. However, dupa7nAChR/ CHRFAM7A expression is relatively low in human brain but elevated in human leukocytes. Furthermore, a7nAChR research in human tissues has been confounded by crossreacting antibodies and nonspecific oligonucleotide primers that crossreact in immunoblotting, immunohistochemistry, and RT-PCR. Yet, 3 independent reports show the human-specific CHRFAM7A changes cell responsiveness to the canonical a7nAChR/CHRNA7 ion-gated channel. Because of its potential for the injury research community, its possible significance to human leukocyte biology, and its relevance to human inflammation, we review the discovery and structure of the dupa7nAChR/ CHRFAM7A gene, the distribution of its mRNA, and its biologic activities and then discuss its possible role(s) in specifying human inflammation and injury. In light of emerging concepts that point to a role for human-specific genes in complex human disease, the existence of a human-specific a7nAChR regulating inflammatory responses in injury underscores the need for caution in extrapolating findings in the a7nAChR literature to man. To this end, we discuss the translational implications of a uniquely human a7nAChR-like gene on new drug target discovery and therapeutics development for injury, infection, and inflammation.