Proteomic profiling reveals structural and adhesion pathways regulated by the inverted CHRFAM7AΔ2bp variant in human neural progenitor cells

The CHRNA7 gene, located on chromosome 15q13.3, encodes the α7 nicotinic acetylcholine receptor (α7 nAChR) subunit and lies within a genomic region characterized by high recombination rates and associations with multiple neuropsychiatric disorders. Within this region, the human specific gene CHRFAM7A arose through partial duplication, rearrangement, and fusion between CHRNA7 and FAM7A. The direct CHRFAM7A allele has been shown to negatively regulate α7 nAChR function. The inverted allele (CHRFAM7AΔ2bp), harboring a two-base pair deletion in exon 6, is linked to schizophrenia, bipolar disorder, and other psychiatric conditions. In this study, we investigated how the presence of the CHRFAM7AΔ2bp allele alters the cellular proteome. Using high-throughput proteomic analysis by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), we characterized protein expression in neuronal progenitors differentiated from isogenic human induced pluripotent stem cell (iPSC) lines representing CHRFAM7AΔ2bp and CHRFAM7A-null genotypes. Comparative analysis identified 129 differentially expressed proteins enriched in pathways related to extracellular matrix organization, collagen biosynthesis, and cell adhesion. Functional assays further demonstrated differences in matrix adhesion between CHRFAM7A-null and CHRFAM7AΔ2bp-derived progenitors. These results suggest that the CHRFAM7AΔ2bp variant influences cellular structure through modulation of adhesion matrix-interaction proteins. This work provides insight into molecular mechanisms that may underlie increased neurodisease vulnerability associated with this genotype.