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Syntaxin1A overexpression and pain insensitivity in individuals with 7q11.23 duplication syndrome
Michael J. Iadarola, Matthew R. Sapio, Amelia J. Loydpierson, Carolyn B. Mervis, Jill C. Fehrenbacher, Michael R. Vasko, Dragan Maric, Daniel P. Eisenberg, Tiffany A. Nash, J. Shane Kippenhan, Madeline H. Garvey, Andrew J. Mannes, Michael D. Gregory, Karen F. Berman
Michael J. Iadarola, Matthew R. Sapio, Amelia J. Loydpierson, Carolyn B. Mervis, Jill C. Fehrenbacher, Michael R. Vasko, Dragan Maric, Daniel P. Eisenberg, Tiffany A. Nash, J. Shane Kippenhan, Madeline H. Garvey, Andrew J. Mannes, Michael D. Gregory, Karen F. Berman
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Research Article Genetics Neuroscience

Syntaxin1A overexpression and pain insensitivity in individuals with 7q11.23 duplication syndrome

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Abstract

Genetic modifications leading to pain insensitivity phenotypes, while rare, provide invaluable insights into the molecular biology of pain and reveal targets for analgesic drugs. Pain insensitivity typically results from Mendelian loss-of-function mutations in genes expressed in nociceptive (pain-sensing) dorsal root ganglion (DRG) neurons that connect the body to the spinal cord. We document a pain insensitivity mechanism arising from gene overexpression in individuals with the rare 7q11.23 duplication syndrome (Dup7), who have 3 copies of the approximately 1.5-megabase Williams syndrome (WS) critical region. Based on parental accounts and pain ratings, people with Dup7, mainly children in this study, are pain insensitive following serious injury to skin, bones, teeth, or viscera. In contrast, diploid siblings (2 copies of the WS critical region) and individuals with WS (1 copy) show standard reactions to painful events. A converging series of human assessments and cross-species cell biological and transcriptomic studies identified 1 likely candidate in the WS critical region, STX1A, as underlying the pain insensitivity phenotype. STX1A codes for the synaptic vesicle fusion protein syntaxin1A. Excess syntaxin1A was demonstrated to compromise neuropeptide exocytosis from nociceptive DRG neurons. Taken together, these data indicate a mechanism for producing “genetic analgesia” in Dup7 and offer previously untargeted routes to pain control.

Authors

Michael J. Iadarola, Matthew R. Sapio, Amelia J. Loydpierson, Carolyn B. Mervis, Jill C. Fehrenbacher, Michael R. Vasko, Dragan Maric, Daniel P. Eisenberg, Tiffany A. Nash, J. Shane Kippenhan, Madeline H. Garvey, Andrew J. Mannes, Michael D. Gregory, Karen F. Berman

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Figure 2

Transcriptomic expression profile of WS/Dup7 genes in DRG and peptidergic innervation of human spinal cord.

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Transcriptomic expression profile of WS/Dup7 genes in DRG and peptidergi...
(A and B) Expression across the 7q11.23 locus in genetically fluorescent mouse DRG neurons separated by FACS into Trpv1+ lineage and non-Trpv1+ cells. (A) Stx1a was the only gene in 7q11.23 exhibiting enriched expression in the Trpv1 neuronal lineage whereas the others were either equally or not expressed in the 2 populations. (B) An approximately 6-fold enrichment is evident for Stx1a compared with other genes in the locus. (C and D) Bioinformatic analyses of a second genetically labeled mouse DRG neuron study. Labeled neurons were separated into 8 phenotypic groups (24). The groups expressing Trpv1 or Stx1a, respectively, are shown in C and D. Stx1a is detected in the 2 main subgroups that express Trpv1 (dotted boxes, C and D) and in a nonpeptidergic group of nociceptors. Abbreviations in C and D relate to sensory modality and axon type. A-β Field LTMR, large-fiber, low-threshold mechanoreceptor responsive to skin stroking; A-β SA1-LTMR, slowly adapting LTMR; A-β RA1-LTMR, rapidly adapting LTMR; A-δ LTMR, lightly myelinated LTMR; C-LTMR, small, unmyelinated C-fiber LTMR; peptidergic nociceptor, peptide-containing nociceptor (generally C-fiber); nonpeptidergic nociceptor: pain-sensing C-fiber neurons without peptides (71, 72). (E) CGRP staining of human DRG neurons overlaps extensively with TRPV1 and serves as a surrogate marker for TRPV1+ neurons. A range of staining from lightly labeled (arrowheads) to darkly labeled (arrows) and unlabeled neurons (asterisks), and a range of sizes, are seen. This is similar to the pattern of staining for TRPV1 in the human as seen in Figures 6 and 7 using in situ hybridization. (F) The axonal projections of CGRP-expressing DRG neurons densely terminate in the superficial layers of human spinal cord dorsal horn, the spinal region that processes nociceptive peripheral input. sFPKM, significant fragments per kilobase per million aligned reads; RPKM, reads per kilobase of transcript per million bases sequenced.

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