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Genes Brain Behav. 2016 Jul;15(6):604-15. doi: 10.1111/gbb.12302.

Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test.

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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.
Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
Department of Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
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.
Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada.
Mammalian Genetics & Genomics, Oak Ridge National Laboratory, Oak Ridge, TN, USA.
The Jackson Laboratory, Bar Harbor, ME, USA.


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.


Casein kinase 1; linkage mapping; microarray; quantitative trait locus; transcript abundance; voltage-gated calcium channels; von Frey

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