{{Short description|Protein-coding gene in humans}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''CHRFAM7A''' is human specific gene located on chromosome 15.<ref name=":4">{{cite journal | vauthors = Sinkus ML, Graw S, Freedman R, Ross RG, Lester HA, Leonard S | date = September 2015 | title = The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function | journal = Neuropharmacology | volume = 96 | issue = Pt B | pages = 274–288 | doi = 10.1016/j.neuropharm.2015.02.006 | pmc = 4486515 | pmid = 25701707 }}</ref><ref name=":0">{{cite journal | vauthors = Ihnatovych I, Saddler RA, Sule N, Szigeti K | date = April 2024 | title = Translational implications of CHRFAM7A, an elusive human-restricted fusion gene | journal = Molecular Psychiatry | volume = 29 | issue = 4 | pages = 1020–1032 | doi = 10.1038/s41380-023-02389-1 | pmc = 11176066 | pmid = 38200291 | doi-access = free }}</ref> The region in which CHRFAM7A is located on chromosome 15 is referred to as chromosome 15q13 where the partial duplication of CHRNA7 occurs.<ref name=":6">{{cite journal | vauthors = Gault J, Robinson M, Berger R, Drebing C, Logel J, Hopkins J, Moore T, Jacobs S, Meriwether J, Choi MJ, Kim EJ, Walton K, Buiting K, Davis A, Breese C, Freedman R, Leonard S | date = September 1998 | title = Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) | journal = Genomics | volume = 52 | issue = 2 | pages = 173–185 | doi = 10.1006/geno.1998.5363 | pmid = 9782083 }}</ref><ref name=":1">{{cite journal | vauthors = Görgülü I, Jagannath V, Pons S, Koniuszewski F, Groszer M, Maskos U, Huck S, Scholze P | date = September 2024 | title = The human-specific nicotinic receptor subunit CHRFAM7A reduces α7 receptor function in human induced pluripotent stem cells-derived and transgenic mouse neurons | journal = The European Journal of Neuroscience | volume = 60 | issue = 5 | pages = 4893–4906 | doi = 10.1111/ejn.16474 | pmid = 39073048 | doi-access = free }}</ref> CHRFAM7A is a fusion gene derived from the partial duplication of the CHRNA7 gene and FAM7A cassettes derived from the ULK4 gene.<ref name=":0" /><ref name=":2">{{cite journal | vauthors = Di Lascio S, Fornasari D, Benfante R | date = March 2022 | title = The Human-Restricted Isoform of the α7 nAChR, CHRFAM7A: A Double-Edged Sword in Neurological and Inflammatory Disorders | journal = International Journal of Molecular Sciences | volume = 23 | issue = 7 | pages = 3463 | doi = 10.3390/ijms23073463 | pmc = 8998457 | pmid = 35408823 | doi-access = free }}</ref><ref name=":1" />
CHRFAM7A encodes for a modified protein subunit known as dupɑ7 or dupɑ7nAChr.<ref name=":2" /><ref name=":3">{{cite journal | vauthors = Costantini TW, Dang X, Coimbra R, Eliceiri BP, Baird A | date = February 2015 | title = CHRFAM7A, a human-specific and partially duplicated α7-nicotinic acetylcholine receptor gene with the potential to specify a human-specific inflammatory response to injury | journal = Journal of Leukocyte Biology | volume = 97 | issue = 2 | pages = 247–257 | doi = 10.1189/jlb.4RU0814-381R | pmc = 4304420 | pmid = 25473097 | doi-access = free }}</ref> Dupɑ7 is a modified subunit of ɑ7 which lacks a portion of the extracellular N-terminal ligand binding domain and the membrane signal peptide.<ref name=":1" /><ref name=":3" /> Dupɑ7 binds with ɑ7 to form heteromeric receptors that function as dominant negative regulators.<ref name=":4" /><ref name=":2" /><ref name=":1" /> This combination leads to reduced calcium influx by reducing the likelihood of the receptor's channel opening.<ref name=":0" /><ref name=":5">{{cite journal | vauthors = Szigeti K, Ihnatovych I, Birkaya B, Chen Z, Ouf A, Indurthi DC, Bard JE, Kann J, Adams A, Chaves L, Sule N, Reisch JS, Pavlik V, Benedict RH, Auerbach A, Wilding G | date = September 2020 | title = CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease | language = English | journal = eBioMedicine | volume = 59 | article-number = 102892 | doi = 10.1016/j.ebiom.2020.102892 | pmc = 7452451 | pmid = 32818803 | doi-access = free }}</ref>
Since CHRFAM7A is only found in humans, it has been studied as a possible factor contributing to differences between human and animal research.<ref name=":4" /><ref name=":5" /> CHRFAM7A has also been associated with psychiatric and cognitive disorders such as schizophrenia and Alzheimer's disease.<ref name=":7">{{cite journal | vauthors = Jakimovski D, Dorn RP, Regno MD, Bartnik A, Bergsland N, Ramanathan M, Dwyer MG, Benedict RH, Zivadinov R, Szigeti K | date = 2024-04-22 | title = Human restricted ''CHRFAM7A'' gene increases brain efficiency | language = English | journal = Frontiers in Neuroscience | volume = 18 | article-number = 1359028 | doi = 10.3389/fnins.2024.1359028 | pmc = 11070550 | pmid = 38711941 | doi-access = free }}</ref><ref name=":4" /><ref name=":2" />
== Structure == CHRFAM7A is a human fusion gene formed by a partial duplication of CHRNA7 exons 5-10 and seven FAM7A cassette exons.<ref name=":0" /><ref name=":2" /><ref name=":13" /> 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.<ref name=":2" /><ref name=":0" /> CHRFAM7A is located on chromosome 15q13-q14 1.6 Mb centromeric to the CHRNA7 gene.<ref name=":8" /><ref name=":11" /><ref name=":2" /> This region of the chromosome has high instability and low copy repeats.<ref name=":0" /><ref name=":1" /> thumb|443x443px|Fig.3 A Schematic depicting CHRFAM7A alleles. CHRFAM7A has multiple variants and polymorphisms.<ref name=":9" /><ref name=":11" /><ref name=":2" /> It has two primary orientations known as direct allele and inverted allele.<ref name=":10" /><ref name=":14" /><ref name=":0" /> Direct allele is orientated in the opposite direction of CHRNA7 and the inverted allele is orientated in the same direction as CHRNA7.<ref name=":12" /><ref name=":2" /> The inverted allele is associated with a 2 base pair deletion in exon 6 causing a frameshift mutation.<ref name=":10" /><ref name=":0" /> CHRFAM7A also has copy number variation where individuals carry 0 to 3 copies of the gene.<ref name=":0" /><ref name=":5" /> 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.<ref name=":12" /><ref name=":13" />
CHRFAM7A encodes for Dupɑ7 which is a truncated version of the ɑ7 nicotinic acetylcholine receptor subunit.<ref name=":11" /><ref name=":2" /> It lacks the first 95 amino acids of ɑ7 as well as the signal peptide and a portion of the extracellular ligand binding domain.<ref name=":11" /><ref name=":1" /> 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.<ref name=":11" /><ref name=":2" /><ref name=":13" /> The molecular weight of dupɑ7 is around 45-50 kDa which is lighter compared to the ɑ7 subunit which is 55-57 kDa.<ref name=":11" /><ref name=":2" />
== Function == CHRFAM7A functions as a dominant negative regulator to the ɑ7 nicotinic acetylcholine receptor.<ref name=":13" /><ref name=":12" /> Its protein product dupɑ7 binds with ɑ7 to form a heteromeric receptor.<ref name=":4" /><ref name=":0" /> This results in a hypomorphic receptor formation reducing acetylcholine microscopic currents, channel opening, and calcium influx.<ref name=":5" /><ref name=":2" /> In some lung cancers, the receptors hypomorphic response to nicotine may decrease cell proliferation, migration, and EMT.<ref name=":0" /><ref name=":2" /> thumb|380x380px|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.<ref name=":5" /><ref name=":2" /> CHRFAM7A is expressed rapidly in human leukocytes and regulated immune response through modulation of NF-κB activation and translocation.<ref name=":3" /><ref name=":0" /><ref name=":2" /> This leads to the release of inflammatory cytokines including IL-6, IL-1ß, and TNF-ɑ.<ref name=":0" /><ref name=":2" /> thumb|384x384px|Fig.5 Characterization of the α7/CHRFAM7A nAChR CHRFAM7A effects neuronal structure through actin cytoskeleton reorganization by acting as an upstream regulator of Rac1.<ref name=":7" /><ref name=":0" /><ref name=":5" /> 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.<ref name=":7" /><ref name=":0" /><ref name=":5" /> It has also been shown to lessen amyloid beta uptake reducing neurotoxicity in humans.<ref name=":5" /><ref name=":0" /><ref name=":2" />
== Family == CHRFAM7A is a member of the nicotinic acetylcholine receptor family.<ref name=":4" /><ref name=":2" /><ref name=":3" /> The nicotinic acetylcholine receptors belong to a superfamily of ligand gated ion channels also known as the cys-loop receptor superfamily.<ref name=":11" /><ref name=":3" /><ref name=":2" /> Other members of this superfamily include GABA A, GABA C, glycinergic receptors, and serotonin receptors.<ref name=":2" /><ref name=":11" /> thumb|394x394px|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.<ref name=":2" /><ref name=":0" /> The FAM7A ULK4 gene component of CHRFMA7A encodes for serine and threonine kinase involved in neuronal process such as neuritogenesis and cellular motility.<ref name=":12" /><ref name=":0" /> The FAM7A GOLGA8B component of CHRFAM7A is linked to the golgin family of proteins which is associated with the Golgi apparatus.<ref name=":0" /><ref name=":2" /> 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.<ref name=":12" /><ref name=":4" />
== Clinical significance == CHRFAM7A is absent in standard preclinical models such as rodents causing a translation gap in drugs targeting the ɑ7 nicotinic acetylcholine receptor.<ref name=":5" /><ref name=":4" /><ref name=":0" /><ref name=":2" /> The translation gap is also influenced by the presence of direct alleles that produce a hypomorphic receptor.<ref name=":0" /><ref name=":5" /> 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.<ref name=":2" /><ref name=":0" /><ref name=":5" />
CHRFAM7A also plays a role in pharmacogenetics.<ref name=":0" /><ref name=":5" /> The presence of the direct allele has been shown to reduce therapeutic treatment such as acetylcholine inhibitors.<ref name=":2" /><ref name=":0" /> The direct allele also reduces neuronal uptake of amyloid beta which can be protective during early stages of Alzheimer's disease.<ref name=":5" /><ref name=":0" /><ref name=":2" /> 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.<ref name=":11" /><ref name=":12" /><ref name=":2" />
CHRFAM7A is present in inflammatory and immune related conditions.<ref name=":2" /><ref name=":0" /> In patients with sepsis, a high CHRFAM7A to CHRNA7 ratio in their blood is associated with poor clinical outcomes and increased mortality rates.<ref name=":2" /><ref name=":0" /> In contrast, reduced expression is associated with elevated levels of inflammation and condition severity in COVID-19.<ref name=":2" /><ref name=":0" /> In spinal cord injuries, the presence of △2bp is associated with increased inflammatory cytokine levels and higher neuropathic pain.<ref name=":3" /><ref name=":0" /><ref name=":2" /> In cell lung carcinomas, the gene acts as a protective factor by reducing nicotine induced cell proliferation and inhibits tumor progression.<ref name=":2" /><ref name=":0" />
In healthy individuals, CHRFAM7A has been linked to brain efficiency and cognitive performance.<ref name=":7" /><ref name=":0" /> Neuroimaging suggest carriers have smaller whole brain volumes but have higher cognitive function.<ref name=":7" /><ref name=":0" />
== Research == 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.<ref name=":0" /><ref name=":1" /><ref name=":2" /> CHRFAM7A was first identified through studies of the CHRNA7 gene on chromosome 15.<ref name=":6" /><ref name=":3" /><ref name=":8">{{cite journal | vauthors = Riley B, Williamson M, Collier D, Wilkie H, Makoff A | date = February 2002 | title = A 3-Mb map of a large Segmental duplication overlapping the alpha7-nicotinic acetylcholine receptor gene (CHRNA7) at human 15q13-q14 | journal = Genomics | volume = 79 | issue = 2 | pages = 197–209 | doi = 10.1006/geno.2002.6694 | pmid = 11829490 }}</ref> In 1998, Gault et al. discovered that the CHRNA7 gene undergoes a partial duplication.<ref name=":6" /><ref name=":2" /><ref name=":3" /> This partial duplication was later shown to create CHRFAM7A.<ref name=":3" /><ref name=":4" />
=== Early 2000s === Later in 2002, Riley et al. confirmed that exons 5-10 of CHRNA7 fuse with a cluster of exons on the FAM7A cassette.<ref name=":8" /><ref name=":2" /><ref name=":3" /> It was later found that four of these exons, A,B,C, and E originated from the ULK4 gene on chromosome 3.<ref name=":8" /><ref name=":2" /> Confirming CHRFAM7A as a human specific fusion gene since this recombination has yet to be found in other species.<ref name=":7" /><ref name=":2" /><ref name=":8" />
In 2003, Gault et al. identified a two base pair deletion △2bp in exon 6.<ref name=":9">{{cite journal | vauthors = Gault J, Hopkins J, Berger R, Drebing C, Logel J, Walton C, Short M, Vianzon R, Olincy A, Ross RG, Adler LE, Freedman R, Leonard S | date = November 2003 | title = Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 123B | issue = 1 | pages = 39–49 | doi = 10.1002/ajmg.b.20061 | pmid = 14582144 }}</ref> 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.<ref name=":10">{{cite journal | vauthors = Flomen RH, Davies AF, Di Forti M, La Cascia C, Mackie-Ogilvie C, Murray R, Makoff AJ | date = November 2008 | title = The copy number variant involving part of the alpha7 nicotinic receptor gene contains a polymorphic inversion | journal = European Journal of Human Genetics | volume = 16 | issue = 11 | pages = 1364–1371 | doi = 10.1038/ejhg.2008.112 | pmid = 18545269 | doi-access = free | hdl = 10447/55175 | hdl-access = free }}</ref>
=== 2010-now === 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.<ref name=":12">{{cite journal | vauthors = Araud T, Graw S, Berger R, Lee M, Neveu E, Bertrand D, Leonard S | date = October 2011 | title = The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of α7*nAChR function | journal = Biochemical Pharmacology | volume = 82 | issue = 8 | pages = 904–914 | doi = 10.1016/j.bcp.2011.06.018 | pmc = 3162115 | pmid = 21718690 }}</ref><ref name=":13">{{cite journal | vauthors = de Lucas-Cerrillo AM, Maldifassi MC, Arnalich F, Renart J, Atienza G, Serantes R, Cruces J, Sánchez-Pacheco A, Andrés-Mateos E, Montiel C | date = January 2011 | title = Function of partially duplicated human α77 nicotinic receptor subunit CHRFAM7A gene: potential implications for the cholinergic anti-inflammatory response | journal = The Journal of Biological Chemistry | volume = 286 | issue = 1 | pages = 594–606 | doi = 10.1074/jbc.M110.180067 | pmc = 3013019 | pmid = 21047781 | doi-access = free }}</ref> 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. <ref>{{cite journal | vauthors = Wang Y, Xiao C, Indersmitten T, Freedman R, Leonard S, Lester HA | date = September 2014 | title = The duplicated α7 subunits assemble and form functional nicotinic receptors with the full-length α7 | journal = The Journal of Biological Chemistry | volume = 289 | issue = 38 | pages = 26451–26463 | doi = 10.1074/jbc.M114.582858 | pmc = 4176222 | pmid = 25056953 | doi-access = free }}</ref><ref name=":11">{{cite journal | vauthors = Lasala M, Corradi J, Bruzzone A, Esandi MD, Bouzat C | date = July 2018 | title = A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries | journal = The Journal of Biological Chemistry | volume = 293 | issue = 27 | pages = 10707–10717 | doi = 10.1074/jbc.RA117.001698 | pmc = 6036215 | pmid = 29784875 | doi-access = free }}</ref>
CHRFAM7A research has also been connected to human disease. In the early 2000s, studies identified strong links between the 15q13.3 locus and schizophrenia.<ref name=":8" /><ref name=":9" /><ref name=":4" /><ref name=":10" /><ref name=":3" /> This led to Szigeti et al.'s research in 2020 that discovered carriers and noncarriers of CHRFAM7A respond differently to therapeutic treatment.<ref name=":14">{{cite journal | vauthors = Szigeti K, Ihnatovych I, Birkaya B, Chen Z, Ouf A, Indurthi DC, Bard JE, Kann J, Adams A, Chaves L, Sule N, Reisch JS, Pavlik V, Benedict RH, Auerbach A, Wilding G | date = September 2020 | title = CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer's disease | journal = eBioMedicine | volume = 59 | article-number = 102892 | doi = 10.1016/j.ebiom.2020.102892 | pmc = 7452451 | pmid = 32818803 | doi-access = free }}</ref>
== References == {{reflist}}
== Further reading == {{refbegin|2}} * {{cite journal | vauthors = Freedman R, Leonard S, Gault JM, Hopkins J, Cloninger CR, Kaufmann CA, Tsuang MT, Farone SV, Malaspina D, Svrakic DM, Sanders A, Gejman P | date = January 2001 | title = Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7) | journal = American Journal of Medical Genetics | volume = 105 | issue = 1 | pages = 20–22 | doi = 10.1002/1096-8628(20010108)105:1<20::AID-AJMG1047>3.0.CO;2-C | pmid = 11424985 | s2cid = 37412240 }} * {{cite journal | vauthors = Trombino S, Cesario A, Margaritora S, Granone P, Motta G, Falugi C, Russo P | date = January 2004 | title = Alpha7-nicotinic acetylcholine receptors affect growth regulation of human mesothelioma cells: role of mitogen-activated protein kinase pathway | journal = Cancer Research | volume = 64 | issue = 1 | pages = 135–145 | doi = 10.1158/0008-5472.CAN-03-1672 | pmid = 14729617 | doi-access = free }} * {{cite journal | vauthors = Bale AS, Meacham CA, Benignus VA, Bushnell PJ, Shafer TJ | date = May 2005 | title = Volatile organic compounds inhibit human and rat neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes | journal = Toxicology and Applied Pharmacology | volume = 205 | issue = 1 | pages = 77–88 | doi = 10.1016/j.taap.2004.09.011 | pmid = 15885267 | bibcode = 2005ToxAP.205...77B }} * {{cite journal | vauthors = Freedman R, Leonard S, Waldo M, Gault J, Olincy A, Adler LE | year = 2006 | title = Characterization of allelic variants at chromosome 15q14 in schizophrenia | journal = Genes, Brain, and Behavior | volume = 5 Suppl 1 | issue = Suppl 1 | pages = 14–22 | doi = 10.1111/j.1601-183X.2006.00190.x | pmid = 16417613 | doi-access = free }} * {{cite journal | vauthors = Dempster EL, Toulopoulou T, McDonald C, Bramon E, Walshe M, Wickham H, Sham PC, Murray RM, Collier DA | date = October 2006 | title = Episodic memory performance predicted by the 2bp deletion in exon 6 of the "alpha 7-like" nicotinic receptor subunit gene | journal = The American Journal of Psychiatry | volume = 163 | issue = 10 | pages = 1832–1834 | doi = 10.1176/appi.ajp.163.10.1832 | pmid = 17012698 }} * {{cite journal | vauthors = Martin LF, Leonard S, Hall MH, Tregellas JR, Freedman R, Olincy A | date = July 2007 | title = Sensory gating and alpha-7 nicotinic receptor gene allelic variants in schizoaffective disorder, bipolar type | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 144B | issue = 5 | pages = 611–614 | doi = 10.1002/ajmg.b.30470 | pmc = 3123155 | pmid = 17192894 }} {{refend}}
== External links == * {{UCSC gene info|CHRFAM7A}} * {{UCSC gene info|CHRNA7}}
Category:Genes on human chromosome 15 Category:Human proteins