The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

Abstract

The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer’s disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dupα7, assembles with α7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated α7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the α7nAChR utilized in drug development research do not have CHRFAM7A (dupα7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease.

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Although the relevance of splice variants in a7 nAChR function still needs to be fully characterized, further efforts have been dedicated to more detailed analysis of the duplicate gene, which corresponds to exons 5-10 of CHRNA7 and is located 1.6 Mb centromeric to CHRNA7, which is now referred to as CHRFAM7A (for a recent detailed review, see Sinkus et al, 2015). The corresponding protein, dup a7, is widely expressed, but in lower levels than a7 nAChRs throughout the body but elevated in peripheral leukocytes (Villiger et al, 2002;Benfante et al, 2011.…”

“…However, what is missing is the detection of the CHRFAM7A transcript, but as noted in a recent review the similarity of this gene with CHRNA7 renders difficult the query in genome-wide association studies. Nonetheless, CHRFAM7A was recently proposed to be associated with several cognitive deficits (Sinkus et al, 2015).…”

A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

“…As recently reviewed by Costantini et al (2) and Sinkus et al (3), it was almost twenty years later that Gault et al (4) sequenced the human α7nAChR gene on chromosome 15q13-14 and found it to be structurally similar to that of all other species. At the same time, however, they noted the presence of a second, human-specific partially duplicated α7nAChR-like gene that localized 1.6 Mb 5′ upstream from human CHRNA7 (4).…”

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

“…Postsynaptically, a7 receptors mediate fast synaptic transmission, and in perisynaptic locations they modulate other inputs to neurons and activate a variety of signaling pathways through volume transmission (Gotti and Clementi, 2004;Jones and Wonnacott, 2004;Dani and Bertrand, 2007;Dickinson et al, 2008;Albuquerque et al, 2009;Sinkus et al, 2015) (Fig. 4).…”

“…Significant reduction of a7 in the brain, particularly in the hippocampus, has been reported in Alzheimer disease (Guan et al, 2000;Kadir et al, 2006) and schizophrenic patients (Schaaf, 2014;Dineley et al, 2015). The a7 gene, CHRNA7 on chromosome 15, is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, intellectual disability, bipolar disorder, autism spectrum disorders, attention deficit hyperactivity disorder, epilepsy, Alzheimer disease, and sensory processing deficit (Sinkus et al, 2009(Sinkus et al, , 2015Schaaf, 2014;Dineley et al, 2015;Deutsch et al, 2016). A partial duplication of CHRNA7 resulting in the chimeric gene CHRFAM7A, which is present only in humans, has been associated with schizophrenia (Sinkus et al, 2009;Neri et al, 2012).…”