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Review
. 2024 Apr;29(4):1020-1032.
doi: 10.1038/s41380-023-02389-1. Epub 2024 Jan 10.

Translational implications of CHRFAM7A, an elusive human-restricted fusion gene

Ivanna Ihnatovych  1 , Ruth-Ann Saddler  1 , Norbert Sule  2 , Kinga Szigeti  3
Affiliations
Review

Translational implications of CHRFAM7A, an elusive human-restricted fusion gene

Ivanna Ihnatovych et al. Mol Psychiatry. 2024 Apr.

Abstract

Genes restricted to humans may contribute to human-specific traits and provide a different context for diseases. CHRFAM7A is a uniquely human fusion gene and a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR). The α7 nAChR has been a promising target for diseases affecting cognition and higher cortical functions, however, the treatment effect observed in animal models failed to translate into human clinical trials. As CHRFAM7A was not accounted for in preclinical drug screens it may have contributed to the translational gap. Understanding the complex genetic architecture of the locus, deciphering the functional impact of CHRFAM7A on α7 nAChR neurobiology and utilizing human-relevant models may offer novel approaches to explore α7 nAChR as a drug target.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Genomic architecture of CHRFAM7A locus.
A Schematic depicting CHRFAM7A alleles. B Copy number and allele frequency of CHRFAM7A in 657 normal controls by locus specific dual genotyping (TaqMan for dosage and Capillary sequencing for 2 bp deletion). C CHRFAM7A locus characteristics demonstrated in USCS genome browser reference sequence with active tracks including mappability which refers to the fidelity of sequence mapping to the reference genome, existing microarrays probes in frequently used commercial microarrays and the genomic architecture of low copy repeats depicted as orange and grey bars. These LCRs have over 95% sequence homology. These tracks indicate limited mappability (density of red bars); sparse probe coverage of CHRFAM7A in SNP arrays undermining detection of association in GWAS studies and complex genomic architecture with low copy repeats. D PCR mapping of the alleles in 6 samples with known CHRFAM7A genotype (depicted on top): UB068 – 0 copy of CHRFAM7A, null; H9 and UB056 - inverted, I; UB019 and UB134 - heterozygous, HZ; UB052 - direct, D. Primer sets are depicted below. To detect a part of CHRNA7, the forward primer was designed to hybridize with a unique sequence in exon A and the reverse primers - within exons 6, 7, 8, 9, and 10. To decipher the exon composition of FAM7A/ULK4 segment, the forward primers are designed in sequences in exon F, D-C, B, E and the reverse primer - in exon 5 on CHRNA7 segment.
Fig. 2
Fig. 2. Gaps in understanding CHRFAM7A effect on α7 nAChR in the neuronal lineage.
A Schematic diagram illustrating α7 nAChR-mediated signaling cascades in neuronal cells. Agonist binding to the α7 nAChR causes the receptor activation and an increase in Ca2+ concentration. Ionotropic receptor function is associated with Ca2+ influx from the extracellular space and calcium-induced calcium release (CICR) from the endoplasmic reticulum. The desensitized, inactive receptor is thought to function as a metabotropic receptor activating inositol 1,4,5-trisphosphate (IP3) induced calcium release (IICR) from the ER. Downstream Ca2+ signaling is implicated in 1) neurotransmitter release; 2) structural LTP (depends on sequential activation of Calcium–calmodulin (CaM)-dependent protein kinase II (CaMKII), protein kinase A (PKA), Extracellular signal-regulated kinase (ERK), and cyclic AMP response element binding protein, CREB; 3) activation of Phosphoinositide 3-kinase (PI3K) and Akt that leads to inactivation of glycogen synthase kinase 3 beta (GSK3β), and downregulation of apoptosis through downregulation of BAX and upregulation of Bcl2 that ultimately results in neuroprotection; 4) activation of RhoA that causes a decrease in actin and tubulin polymerization and attenuates neurite outgrowth and microtubule assembly; 5) activation of CDC42 that leads to filopodia membrane specialization in neurite outgrowth, growth cone, and dendritic spine. B CHRFAM7A effect on α7 nAChR-mediated signaling pathways in neurons has been partially elucidated. α7/CHRFAM7A nAChR being a hypomorphic receptor demonstrates decreased activation by electrophysiology and diminished Ca2+ influx. The hypomorphic receptor has decreased agonist (α-BTX) binding and mitigates amyloid beta 1-42 (Aβ1-42) uptake. α7/CHRFAM7A nAChR leads to decreased channel open probability shifting the time spent in CICR to IICR associated with activation of small GTPase Rac1. Downstream, Rac1 switches from CDC42/filopodia to Rac1/lamellipodia membrane structure at all levels of the neuronal unit: neurite outgrowth, growth cone, and dendritic spine. Compared to α7 nAChR (A), α7/CHRFAM7A nAChR associated phenotypes and signaling demonstrate significant gaps in knowledge (B) Dotted lines represent predicted pathways (created with BioRender.com).
Fig. 3
Fig. 3. Gaps in understanding CHRFAM7A effect on α7 nAChR in the mononuclear cell lineage (microglia and macrophage).
A Schematic diagram illustrating α7 nAChR-mediated anti-inflammatory signaling cascades. Activation of α7 nAChR leads to an inhibition of inflammatory cytokines by blocking nuclear factor -κB (NFκB) activity through: 1) Janus kinase 2 (JAK2)-signal transducer and activator-3 (STAT3); STAT3 activates interleukin-1 receptor-associated kinase M (IRAK-M). 2) Gαi-mediated pathway involving activation of phospholipase C (PLC), production of inositol 1,4,5-trisphosphate (IP3), its binding to the receptor (IP3R) in the endoplasmic reticulum (ER), which leads to Ca2+ release from the ER and causes deactivation of c-jun-N-terminal kinase (JNK), p38, and p44/42 mitogen-activated protein kinases. Activation of JAK2 also leads to activation of Phosphoinositide 3-kinase (PI3K) and Akt that phosphorylates and inactivates glycogen synthase kinase 3 beta (GSK3β), which, in turn, leads to activation and nuclear translocation of Nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 induces the expression of anti-inflammatory heme oxygenase-1 (HO-1). Activation of α7 nAChR results in decreased inflammation, MMP9 expression and migration, leading to neuroprotection. B CHRFAM7A effect on α7 nAChR-mediated anti-inflammatory signaling. While signaling of the α7/CHRFAM7A nAChR in mononuclear cells are mostly unknown, emerging evidence suggests that the hypomorphic α7/CHRFAM7A nAChR releases NFκB inhibition leading to activation of proinflammatory cytokines (IL6, IL1β, TNFα). CHRFAM7A is associated with additional inflammatory phenotypes, including immune cell mobilization, a decrease in fibrosis and reduction in M2 macrophages and chemotaxis). Dotted lines represent predicted pathways (created with BioRender.com).
Fig. 4
Fig. 4. Role of α7 nAChR in cancer phenotypes.
A Schematic diagram illustrating α7 nAChR-mediated signaling pathways regulating cell proliferation, angiogenesis, and metastasis (created with BioRender.com). Activation of α7 nAChR by nicotine leads to the activation of Ca2+/calmodulin-dependent signaling pathways increasing: (1) proliferation (Phosphoinositide 3-kinase (PI3K)/Akt; Mitogen-activated protein kinase/ERK kinase (MEK)/ Extracellular signal-regulated kinase (ERK); RAF1/Rb, and Sp1/GATA1); (2) angiogenesis (PI3K)/Akt/NFκB, FGF2); (3) metastasis, (4) epithelial-mesenchymal transition (EMT), and (5) migration (PI3K, MEK/ERK, focal adhesion kinase (FAK), and SOX2). B CHRFAM7A effect on α7 nAChR-mediated signaling pathways in cancer. Activation of α7/CHRFAM7A nAChR receptor by nicotine results in opposite phenotypes consistent with the hypomorphic response to an agonist: a decrease in proliferation, metastasis, EMT, and migration. Signal transduction is unknown (A) (created with BioRender.com).
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