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Functional Characterization of Structural Variants of CHRFAM7A

Abstract ID: 32411

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Ivanna Ihnatovych, PhD1; Tapan Nayak, PhD1; Aya Ouf, MD1; Norbert Sule, MD, PhD2; Barbara Birkaya, PhD1; Trinithas Boyi, MS1; Lee Chaves, PhD1; Anthony Auerbach, PhD1 and Kinga Szigeti, MD, PhD3, (1)SUNY at Buffalo, Buffalo, NY, USA, (2)Roswell Park Cancer Institute, Buffalo, NY, USA, (3)University at Buffalo, BUFFALO, NY, USA

Background: The α7 nicotinic acetylcholine receptor (α7nAChR) is a ligand-gated ion channel implicated in cognition and neuropsychiatric disorders. A unique feature of the α7nAChR is the presence in different copy number variations (CNV) and orientation of CHRFAM7A, a human specific fusion gene, which harbors exons 5-10 of CHRNA7 and exons A-E of the FAM7 sequence. An association between CHRFAM7A dosage and Alzheimer’s Disease (AD) has been reported (CNV GWAS); CHRFAM7A lower CNV and expression levels is associated with AD. In contrast, its upregulation and a correlation with the inverted orientation is observed in schizophrenia and bipolar disorder. While the α7nAChR has been a promising target for neuropsychiatric disorders, the effect observed in animal models failed to translate into human clinical trials. We hypothesized that CHRFAM7A, a human specific gene with properties that enable incorporation into the α7nAChR, may account for the translational gap; understanding its function may offer novel insights when exploring α7nAChR as a drug target. Method: To study the functional consequences of the presence of the CHRFAM7A, three iPSC lines (0 copy, 1 copy direct, and 1 copy inverted) were developed and Medial Ganglionic Eminence progenitors and neurons were generated. The 0 copy line was rescued with CHRFAM7A transfection to control for genetic heterogeneity. As readouts for genotype-phenotype correlation, α7nAChR synaptic transmission and Aβ1-42 uptake were tested. Result: Synaptic transmission in the presence of CHRFAM7A (1 copy direct line) demonstrated that PNU-modulated desensitization of α7nAChR currents increased as a function of CHRFAM7A dosage. While CHRFAM7A (direct orientation) mitigated the dose response of Aβ1–42 uptake suggesting a protective effect beyond physiological concentrations, its presence in the inverted orientation did not have this effect. Furthermore, in the presence of CHRFAM7A (direct orientation) Aβ1–42 uptake activated neuronal interleukin 1β and TNFα. Preliminary data on potential mechanisms are discussed and the involvement of autophagy and inflammasome signaling is elaborated. Conclusion: A current study revealed functional differences between structural variants of CHRFAM7A: the 1 copy direct line mitigated the dose response of Aβ1–42 uptake and modulated α7nAChR. Lead optimization may identify more potent molecules when the screen has a model harboring CHRFAM7A.