title: Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test.
abstract: Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation.
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|School of Nursing, University of Connecticut, Storrs, CT, USA.|Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Young
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Bryant
authors.affiliation: Department of Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Cook
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Nair
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Dreher
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.|Department of Human Genetics, University of Chicago, Chicago, IL, USA.|Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Palmer
authors.affiliation: Department of Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Chung
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
authors.forename: J S
authors.initials: JS
authors.lastname: Mogil
authors.affiliation: Mammalian Genetics & Genomics, Oak Ridge National Laboratory, Oak Ridge, TN, USA.|The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Chesler
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Lariviere
mesh_terms: D000588:Amines / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D047389:Casein Kinase I / Q000235:genetics* / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D000077206:Gabapentin; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000235:genetics*; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology; D040641:Quantitative Trait Loci; D012684:Sensory Thresholds; D014110:Touch / Q000187:drug effects / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000588:Amines; D000700:Analgesics; C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D011743:Pyrimidines; C000595889:intraflagellar transport 27 protein, mouse; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C522839:PF-670462; D047389:Casein Kinase I; D020691:rab GTP-Binding Proteins
keywords: Casein kinase 1; linkage mapping; microarray; quantitative trait locus; transcript abundance; voltage-gated calcium channels; von Frey