title: The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of α7*nAChR function.
abstract: The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a candidate gene for schizophrenia and an important drug target for cognitive deficits in the disorder. Activation of the α7*nAChR, results in opening of the channel and entry of mono- and divalent cations, including Ca(2+), that presynaptically participates to neurotransmitter release and postsynaptically to down-stream changes in gene expression. Schizophrenic patients have low levels of α7*nAChR, as measured by binding of the ligand [(125)I]-α-bungarotoxin (I-BTX). The structure of the gene, CHRNA7, is complex. During evolution, CHRNA7 was partially duplicated as a chimeric gene (CHRFAM7A), which is expressed in the human brain and elsewhere in the body. The association between a 2bp deletion in CHRFAM7A and schizophrenia suggested that this duplicate gene might contribute to cognitive impairment. To examine the putative contribution of CHRFAM7A on receptor function, co-expression of α7 and the duplicate genes was carried out in cell lines and Xenopus oocytes. Expression of the duplicate alone yielded protein expression but no functional receptor and co-expression with α7 caused a significant reduction of the amplitude of the ACh-evoked currents. Reduced current amplitude was not correlated with a reduction of I-BTX binding, suggesting the presence of non-functional (ACh-silent) receptors. This hypothesis is supported by a larger increase of the ACh-evoked current by the allosteric modulator 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596) in cells expressing the duplicate than in the control. These results suggest that CHRFAM7A acts as a dominant negative modulator of CHRNA7 function and is critical for receptor regulation in humans.
authors: Department of Neurosciences Medical Faculty, University of Geneva, Geneva, Switzerland. Sherry.Leonard@ucdenver.edu
authors: Tanguy
authors: T
authors: Araud
authors: Sharon
authors: S
authors: Graw
authors: Ralph
authors: R
authors: Berger
authors: Michael
authors: M
authors: Lee
authors: Estele
authors: E
authors: Neveu
authors: Daniel
authors: D
authors: Bertrand
authors: Sherry
authors: S
authors: Leonard
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D055724:Electrophysiological Phenomena; D005260:Female; D020131:Genes, Duplicate; D008040:Genetic Linkage; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D005810:Multigene Family; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D011485:Protein Binding; D012313:RNA / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics; D012907:Smoking / Q000235:genetics; D014162:Transfection; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D002038:Bungarotoxins; C579167:Chrna7 protein, human; D007555:Isoxazoles; D008024:Ligands; D010671:Phenylurea Compounds; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D012313:RNA