Elsevier

Neuropharmacology

Volume 96, Part B, September 2015, Pages 274-288
Neuropharmacology

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

https://doi.org/10.1016/j.neuropharm.2015.02.006Get rights and content

Highlights

  • The α7 nicotinic receptor gene, CHRNA7, is associated with many mental illnesses.

  • CHRNA7 on chromosome 15 was partially duplicated forming a new gene, CHRFAM7A.

  • The gene product of CHRFAM7A, dupα7, assembles with α7 subunits (α7dupα7*).

  • Dupα7 is a dominant negative regulator of α7nAChR function.

  • CHRFAM7A is not present in either rodents or primates, only in humans.

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.

This article is part of the Special Issue entitled ‘The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition’.

Graphical abstract

The human α7 nicotinic receptor gene, CHRNA7, is partially duplicated, forming a new gene, CHRFAM7A (A). The gene product, dupα7 (C), assembles with α7 (B) subunits. The α7dupα7* receptor has fewer binding sites (D), and is a potent dominant negative regulator of α7nAChR function. CHRFAM7A is not found in either rodents or primates, resulting in important implications for neuropsychiatric genetics and drug development.

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Section snippets

The human alpha 7 nicotinic acetylcholine receptor gene cluster on chromosome 15

The α7 neuronal nicotinic receptor gene, CHRNA7 on Chromosome 15, is widely expressed in both the brain and periphery with multiple important roles in cognition and the immune system. Decreased expression and function of CHRNA7 have been associated with many diseases including schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, autism, epilepsy, and learning disorders. Regulation of CHRNA7 expression and function is complex. More than a dozen

The alpha7 nicotinic acetylcholine receptor gene, CHRNA7

The α7 neuronal nicotinic acetylcholine receptor, α7nAChR, is a member of the nicotinic acetylcholine receptor family. These receptors are ligand-gated ion channels of five subunits, stimulated endogenously by acetylcholine, resulting in flux of the cations Na+, K+, and Ca++ (Changeux, 2012, Vijayaraghavan et al., 1992). Eleven nicotinic receptor subunit genes are expressed in the human brain, including α2–7, 9, 10, and β2–4 (Elgoyhen et al., 2009, Lindstrom, 1997), which form multiple

The duplicated alpha 7 gene, CHRFAM7A

As described in Section 1, The CHRNA7 gene was partially duplicated relatively late in evolutionary history, forming a new gene, CHRFAM7A, mapping 1.6 Mb centromeric to the parent gene. As a recent discovery, much less is known about the duplication.

Mutation in the CHRNA7/CHRFAM7A gene cluster

Mutation screening in both of these genes was done in mRNA as there is more than 99% conservation in the duplicated CHRNA7 exons 5–10 (Gault et al., 2003).

Copy number variation in CHRNA7 and CHRFAM7A

CHRFAM7A varies in copy number; some individuals have only one copy of CHRFAM7A and a rare subject has no copies. Copy number of the CHRNA7 gene is not as variable; deletion and duplication are rare. We developed a copy number assay for alleles of CHRFAM7A, utilizing real-time quantitative PCR and exon-specific primers (Flomen et al., 2006, Sinkus et al., 2009). Table 1 shows copy number data for the CHRNA7 gene (7) and the CHRFAM7A gene (7A) in 772 individuals, 322 control subjects and 450

Genetics of CHRNA7 and CHRFAM7A in mental illnesses

The possible polymorphisms that can be used for genetic studies in these two genes are limited and complex. The CHRNA7 proximal promoter (not duplicated) is polymorphic with 21 known mutations (Leonard, 2014, Leonard et al., 2002), most of which decrease transcription, suggesting that heterogeneity at this locus is an important consideration. In initial studies, we did find association of a single promoter SNP at -86C/T to schizophrenia, but the association was stronger for grouped functional

Cognition and the CHRNA7/CHRFAM7A gene cluster

Expression and function of α7nAChR affects multiple disorders. All of the mental illnesses discussed above are characterized by cognitive disorders, such as attention and working memory, in which α7nAChRs are known to play a role. Additional mental disorders in which cognition and the α7nAChR have been implicated include Down's syndrome (Deutsch et al., 2014), and Parkinson's disease (Quik et al., 2013). There are common and measurable phenotypes for cognitive deficits that will be useful for

Drug development

The efficacy of therapeutic agents targeted toward the α7nAChR was first suggested in studies of atypical neuroleptics. The atypical antipsychotic, clozapine, although having adverse side effects on neutrophil count and also on weight gain, is the most effective treatment for schizophrenia to date (McEvoy et al., 2006, Miyamoto et al., 2012). Clozapine, has a complex pharmacology with a higher affinity for 5HT2A serotonin receptors than for dopamine D2, which partially defines atypicals (

Summary and future directions

The CHRNA7 gene cluster is ubiquitously expressed in the human body and has roles in CNS and peripheral development, cognitive performance, and inflammation. The early appearance of α7nAChRs in evolution as an important source of calcium entry into the cell, may explain its residual peripheral functions and development of synaptic roles. The CHRNA7 gene is the parent of other nicotinic receptors, and of a recent additional duplication to form the new gene, CHRFAM7A, only found in humans.

Acknowledgments

Special thanks to Ralph Berger, Judith Logel, Margaret Short, and William Proctor, Ph.D. for technical assistance. The research was funded by NIH grants DA09457, MH81177, and the Veterans Affairs Medical Research Service (Merit Review) to SL.

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