CHRFAM7A

CHRFAM7A is human specific gene located on chromosome 15. The region in which CHRFAM7A is located on chromosome 15 is referred to as chromosome 15q13 where the partial duplication of CHRNA7 occurs. CHRFAM7A is a fusion gene derived from the partial duplication of the CHRNA7 gene and FAM7A cassettes derived from the ULK4 gene.

CHRFAM7A encodes for a modified protein subunit known as dupɑ7 or dupɑ7nAChr. Dupɑ7 is a modified subunit of ɑ7 which lacks a portion of the extracellular N-terminal ligand binding domain and the membrane signal peptide. Dupɑ7 binds with ɑ7 to form heteromeric receptors that function as dominant negative regulators. This combination leads to reduced calcium influx by reducing the likelihood of the receptor's channel opening.

Since CHRFAM7A is only found in humans, it has been studied as a possible factor contributing to differences between human and animal research. CHRFAM7A has also been associated with psychiatric and cognitive disorders such as schizophrenia and Alzheimer's disease.

CHRFAM7A is a human fusion gene formed by a partial duplication of CHRNA7 exons 5-10 and seven FAM7A cassette exons. The FAM7A cassette is composed of exons A,B,C, & E which are derived from a partial duplication of the ULK4 gene and exons D & F which are related to the GOLGA8B gene. CHRFAM7A is located on chromosome 15q13-q14 1.6 Mb centromeric to the CHRNA7 gene. This region of the chromosome has high instability and low copy repeats.

Fig.3 A Schematic depicting CHRFAM7A alleles.

CHRFAM7A has multiple variants and polymorphisms. It has two primary orientations known as direct allele and inverted allele. Direct allele is orientated in the opposite direction of CHRNA7 and the inverted allele is orientated in the same direction as CHRNA7. The inverted allele is associated with a 2 base pair deletion in exon 6 causing a frameshift mutation. CHRFAM7A also has copy number variation where individuals carry 0 to 3 copies of the gene. It also has a mutation at position 654 bp and a C→T transition at 1466 bp which results in a serine to leucine substitution at aa 489.

CHRFAM7A encodes for Dupɑ7 which is a truncated version of the ɑ7 nicotinic acetylcholine receptor subunit. It lacks the first 95 amino acids of ɑ7 as well as the signal peptide and a portion of the extracellular ligand binding domain. This results in dupɑ7 missing loops A and D of the acetylcholine binding domain site but still has all four transmembrane domains M1-M4, the intracellular M3-M4 loop, and the C-terminal. The molecular weight of dupɑ7 is around 45-50 kDa which is lighter compared to the ɑ7 subunit which is 55-57 kDa.

CHRFAM7A functions as a dominant negative regulator to the ɑ7 nicotinic acetylcholine receptor. Its protein product dupɑ7 binds with ɑ7 to form a heteromeric receptor. This results in a hypomorphic receptor formation reducing acetylcholine microscopic currents, channel opening, and calcium influx. In some lung cancers, the receptors hypomorphic response to nicotine may decrease cell proliferation, migration, and EMT.

Fig.4 Role of alpha-7 nicotinic receptor in cancer comparison to CHRFAM7A protein subunit.

The presence of the direct allele can reduce therapeutic response to acetylcholine inhibitors because of its hypomorphism. CHRFAM7A is expressed rapidly in human leukocytes and regulated immune response through modulation of NF-kB activation and translocation. This leads to the release of inflammatory cytokines including IL-6, IL-1ß, and TNF-ɑ.

Fig.5 Characterization of the α7/CHRFAM7A nAChR

CHRFAM7A effects neuronal structure through actin cytoskeleton reorganization by acting as an upstream regulator of Rac1. This promotes the shift from filopodia to lamellipodia membrane structures affecting cell bodies, growth cone, and dendritic spines which may lead to an increase in brain efficiency and neuron connection. It has also been shown to lessen amyloid beta uptake reducing neurotoxicity in humans.

CHRFAM7A is a member of the nicotinic acetylcholine receptor family. The nicotinic acetylcholine receptors belong to a superfamily of ligand gated ion channels also known as the cys-loop receptor superfamily. Other members of this superfamily include GABA A, GABA C, glycinergic receptors, and serotonin receptors.

Fig.2 Example of Ligand Gated Channel

Since CHRFAM7A is a human specific gene its family origins are complex. As a fusion gene, it is also linked to the ULK4 gene family and GOLGA8B. The FAM7A ULK4 gene component of CHRFMA7A encodes for serine and threonine kinase involved in neuronal process such as neuritogenesis and cellular motility. The FAM7A GOLGA8B component of CHRFAM7A is linked to the golgin family of proteins which is associated with the Golgi apparatus. The CHRNA7 gene which CHRFAM7A is derived from is one of the oldest members of the cys-loop receptor family and has stayed similar across many species.

CHRFAM7A is absent in standard preclinical models such as rodents causing a translation gap in drugs targeting the ɑ7 nicotinic acetylcholine receptor. The translation gap is also influenced by the presence of direct alleles that produce a hypomorphic receptor. These factors are not usually accounted for in preclinical screenings, it has been suggested that failed clinical trials should be reproduced so models carry CHRFAM7A and can model human drug responses.

CHRFAM7A also plays a role in pharmacogenetics. The presence of the direct allele has been shown to reduce therapeutic treatment such as acetylcholine inhibitors. The direct allele also reduces neuronal uptake of amyloid beta which can be protective during early stages of Alzheimer's disease. The △2bp polymorphism in exon 6 has been linked as a risk factor for P50 auditory sensory gating deficits which is also linked to schizophrenia.

CHRFAM7A is present in inflammatory and immune related conditions. In patients with sepsis, a high CHRFAM7A to CHRNA7 ratio in their blood is associated with poor clinical outcomes and increased mortality rates. In contrast, reduced expression is associated with elevated levels of inflammation and condition severity in COVID-19. In spinal cord injuries, the presence of △2bp is associated with increased inflammatory cytokine levels and higher neuropathic pain. In cell lung carcinomas, the gene acts as a protective factor by reducing nicotine induced cell proliferation and inhibits tumor progression.

In healthy individuals, CHRFAM7A has been linked to brain efficiency and cognitive performance. Neuroimaging suggest carriers have smaller whole brain volumes but have higher cognitive function.

While we do not know the exact date of when CHRFAM7A appeared in the human lineage we can assume that it appeared approximately 3.5 million years ago after humans evolved from chimpanzees due to it being a human specific gene. CHRFAM7A was first identified through studies of the CHRNA7 gene on chromosome 15. In 1998, Gault et al. discovered that the CHRNA7 gene undergoes a partial duplication. This partial duplication was later shown to create CHRFAM7A.

Later in 2002, Riley et al. confirmed that exons 5-10 of CHRNA7 fuse with a cluster of exons on the FAM7A cassette. It was later found that four of these exons, A,B,C, and E originated from the ULK4 gene on chromosome 3. Confirming CHRFAM7A as a human specific fusion gene since this recombination has yet to be found in other species.

In 2003, Gault et al. identified a two base pair deletion △2bp in exon 6. By 2008, Flomen et al. discovered that this deletion is associated with a genomic inversion that creates two different versions of CHRFAM7A in humans one known as the direct orientation and the other known as the inverted orientation.

In 2011, Araud et al. and de Lucas-Cerrilo et al. provided evidence that dupɑ7 combines with ɑ7 nicotinic acetylcholine receptor and acts as a negative regulator. Later in 2014 & 2018, Wang et al. and Lasala et al. exhibited that the combination of subunits formed truncated heteromeric receptors known as heteropentameric receptors or heteropentamers.

CHRFAM7A research has also been connected to human disease. In the early 2000s, studies identified strong links between the 15q13.3 locus and schizophrenia. This led to Szigeti et al.'s research in 2020 that discovered carriers and noncarriers of CHRFAM7A respond differently to therapeutic treatment.

• Human CHRFAM7A genome location and CHRFAM7A gene details page in the UCSC Genome Browser.
• Human CHRNA7 genome location and CHRNA7 gene details page in the UCSC Genome Browser.