Invited reviewThe human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function
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.
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.
References (195)
- et al.
Development of the alpha 7 nicotinic cholinergic receptor in rat hippocampal formation
Dev. Brain Res.
(2002) - et al.
Identification of acetylcholine-receptor channel-lining residues in the entire M2 segment of the alpha-subunit
Neuron
(1994) - et al.
Kynurenic acid as an antagonist of alpha 7 nicotinic acetylcholine receptors in the brain: facts and challenges
Biochem. Pharmacol.
(2013) - et al.
CHRNA7 haplotypes are associated with impaired attention in euthymic bipolar disorder
J. Affect. Dis.
(2011) - et al.
The duplicated alpha 7 nicotinic receptor gene CHRFAM7A is a dominant negative regulator of CHRNA7 expression
Biochem. Pharmacol.
(2011) - et al.
Expression of the α7 nAChR subunit duplicate form (CHRFAM7A) is down-regulated in the monocytic cell line THP-1 on treatment with LPS
J. Immunol.
(2011) - et al.
[3H]Nicotine binding in peripheral blood cells of smokers is correlated with the number of cigarettes smoked per day
Neuropharmacology
(2000) - et al.
Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy
Lancet
(2002) - et al.
Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia
Neuropsychopharmacology
(2000) - et al.
Developmental expression of alpha 7 neuronal nicotinic receptor messenger RNA in rat sensory cortex and thalamus
Neuroscience
(1995)