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Review
. 2015 Sep;96(Pt B):274-88.
doi: 10.1016/j.neuropharm.2015.02.006. Epub 2015 Feb 19.

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

Melissa L Sinkus  1 , Sharon Graw  2 , Robert Freedman  3 , Randal G Ross  4 , Henry A Lester  5 , Sherry Leonard  6
Affiliations
Review

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

Melissa L Sinkus et al. Neuropharmacology. 2015 Sep.

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'.

Keywords: Alzheimer's; CHRFAM7A; CHRNA7; Gene duplication; Gene mutation; Nicotinic receptor; Schizophrenia.

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Figures

Figure 1
Figure 1
Duplication of exons 5-10 of the CHRNA7 gene and formation of the chimeric gene CHRFAM7A on chromosome 15q13.3. (A) Prior to the duplication of CHRNA7, exons A, B, C, and E were duplicated from ULK4 on chromosome 3 and exons D, F, and G were duplicated from other regions of chromosome 15. Copies of these exons, A-F (FAM7A) are present at least four times on chromosome 15. (B) Subsequently, exons 5-10 of CHRNA7 and 3′ DNA (~250Kb) were duplicated, interrupting a copy of A-F, FAM7A(1), centromeric to CHRNA7 by 1.6Mb forming the chimeric gene, CHRFAM7A. The original orientation of CHRFAM7A relative to CHRNA7 was head to head. (C) A 2bp deletion in exon 6 of CHRFAM7A is associated with an inversion of the gene. CHRFAM7AΔ2bp is in the same orientation as CHRNA7 (tail to head). CHRNA7 exons in red; FAM7A exons in blue; CHRNA7 exons in red; CHRNA7 promoter in yellow.
Figure 2
Figure 2
Order and sequence of upstream exons of CHRFAM7A. (A) Genomic order of the upstream exons of CHRFAM7A. Diagram is not to scale. The sizes of the exons and the distance between are indicated in base pairs. Exons duplicated from the ULK4 gene are shown in yellow; those with homology to GOLGA8B are in green; CHRNA7 exon 5 in blue. (B) DNA sequence of the 5′ upstream exons of CHRFAM7A with exons indicated by color, below. Putative translation start codons are highlighted in fuchsia in exon B for CHRFAM7A and exon 6 for CHRFAM7AΔ2bp. The 2bp deletion (TG) in exon 6 is in bold.
Figure 3
Figure 3
Translation products from the CHRFAM7A gene. (A) CHRFAM7A mRNA. The most common transcript includes only upstream exons D, C, B, and A. (B) Putative translation products. (B.1) Normal translated sequence with methionine start codon in exon B. Peptide contains 26 aa coded by exons A and B before entering in frame sequence of CHRNA7 at aa 117. (B.2) A truncated peptide is formed when the 2bp deletion is present if translation begins in exon B. The 2bp deletion is in the codon for aa167 and changes the reading frame, leading to a stop codon. (B.3) Initiation of translation in exon 6 in the CHRFAM7AΔ2bp mRNA. Two methionine codons are present in exon 6. Translation starts lead to either 6 or 13 aa out of frame before the 2bp deletion in the codon for aa167. After the 2bp deletion, aa sequence reverts to that of CHRNA7. MSR, membrane spanning region; aa, amino acid.
Figure 4
Figure 4
Putative topology of CHRNA7, CHRFAM7A, and CHRFAM7AΔ2bp gene products. (A) The normal α7 subunit with three glycosylation sites and signal peptide. (B) CHRFAM7A gene product (dupα7), missing the signal peptide and two glycosylation sites. (C) CHRFAM7AΔ2bp gene product (dupΔα7), missing the signal peptide, all glycosylation sites, and the cysteine bridge. (D) Pentameric structure of the normal α7nAChR on the left and a pentamer containing the peptide of the duplicated subunit on the right. Note that incorporation of a single duplicated gene subunit eliminates two agonist binding sites, which are localized at the extracellular subunit interfaces.
Figure 5
Figure 5
Relative expression of CHRFAM7A in primary lymphocytes of control and schizophrenic subjects. Real-time PCR was utilized to quantify expression of CHRFAM7A in primary lymphocytes from control and schizophrenic, non-smokers and smokers. Fifteen subjects in each of the four groups were analyzed. Results were normalized to the housekeeping gene SLC9A1, a Na+/H+ antiporter using mean normalized expression (MNESLC) and actual efficiencies of each run. Expression of the SLC9A1 gene was not changed in any of the groups. Expression of the CHRFAM7A gene was significantly increased in lymphocytes from schizophrenic patients. Smoking did not significantly decrease transcription of CHRFAM7A in controls. In schizophrenic smokers, the levels of CHRFAM7A mRNA were not changed, remaining higher than control smokers. (*, p<0.05; **, p<0.01)
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