title: Regulation of Nav1.7: A Conserved SCN9A Natural Antisense Transcript Expressed in Dorsal Root Ganglia.
abstract: The Nav1.7 voltage-gated sodium channel, encoded by SCN9A, is critical for human pain perception yet the transcriptional and post-transcriptional mechanisms that regulate this gene are still incompletely understood. Here, we describe a novel natural antisense transcript (NAT) for SCN9A that is conserved in humans and mice. The NAT has a similar tissue expression pattern to the sense gene and is alternatively spliced within dorsal root ganglia. The human and mouse NATs exist in cis with the sense gene in a tail-to-tail orientation and both share sequences that are complementary to the terminal exon of SCN9A/Scn9a. Overexpression analyses of the human NAT in human embryonic kidney (HEK293A) and human neuroblastoma (SH-SY5Y) cell lines show that it can function to downregulate Nav1.7 mRNA, protein levels and currents. The NAT may play an important role in regulating human pain thresholds and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A locus, such as Inherited Primary Erythromelalgia, Paroxysmal Extreme Pain Disorder and Painful Small Fibre Neuropathy, but who do not contain mutations in the sense gene. Our results strongly suggest the SCN9A NAT as a prime candidate for new therapies based upon augmentation of existing antisense RNAs in the treatment of chronic pain conditions in man.
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Koenig
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom; Department of Anesthesiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, Düsseldorf, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Werdehausen
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom.
authors.forename: John E
authors.initials: JE
authors.lastname: Linley
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom.
authors.forename: Abdella M
authors.initials: AM
authors.lastname: Habib
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Vernon
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom.
authors.forename: Stephane
authors.initials: S
authors.lastname: Lolignier
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom; Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Eijkelkamp
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, Gower street, London, United Kingdom.
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Okorokov
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, United Kingdom.
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Medicine, Seoul National University, Seoul, South Korea.
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, United Kingdom.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
mesh_terms: D000818:Animals; D003001:Cloning, Molecular; D003198:Computer Simulation; D017124:Conserved Sequence; D005727:Ganglia, Spinal / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism; D016372:RNA, Antisense / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; D016372:RNA, Antisense; D012333:RNA, Messenger; C486866:SCN9A protein, human; C503479:Scn9a protein, mouse