The human-restricted isoform of the alpha7 nAChR, CHRFAM7A: a double-edged sword in neurological and inflammatory disorders

CHRFAM7A is a relatively recent and exclusively human gene arising from the partial duplication of exons 5 to 10 of the ?7 neuronal nicotinic acetylcholine receptor subunit (?7 nAChR) encoding gene, CHRNA7. CHRNA7 is related to several disorders that involve cognitive deficits, including neuropsychiatric, neurodegenerative, and inflammatory disorders. In extra-neuronal tissues, ?7nAChR plays an important role in proliferation, differentiation, migration, adhesion, cell contact, apoptosis, angiogenesis, and tumor progression, as well as in the modulation of the inflammatory response through the "cholinergic anti-inflammatory pathway". CHRFAM7A translates the dup?7 protein in a multitude of cell lines and heterologous systems, while maintaining processing and trafficking that are very similar to the full-length form. It does not form functional ion channel receptors alone. In the presence of CHRNA7 gene products, dup?7 can assemble and form heteromeric receptors that, in order to be functional, should include at least two ?7 subunits to form the agonist binding site. When incorporated into the receptor, in vitro and in vivo data showed that dup?7 negatively modulated ?7 activity, probably due to a reduction in the number of ACh binding sites. Very recent data in the literature report that the presence of the duplicated gene may be responsible for the translational gap in several human diseases. Here, we will review the studies that have been conducted on CHRFAM7A in different pathologies, with the intent of providing evidence regarding when and how the expression of this duplicated gene may be beneficial or detrimental in the pathogenesis, and eventually in the therapeutic response, to CHRNA7-related neurological and non-neurological diseases.