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Papers of the Week

Papers: 20 Jan 2024 - 26 Jan 2024

2024 Jan 23

JCI Insight


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


Iadarola MJ, Sapio MR, Loydpierson AJ, Mervis CB, Fehrenbacher JC, Vasko MR, Maric D, Eisenberg DP, Nash TA, Kippenhan JS, Garvey MH, Mannes AJ, Gregory MD, Berman KF


Genetic modifications leading to pain insensitivity phenotypes are rare but can provide invaluable insights into the molecular biology of pain and reveal novel 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 novel pain insensitivity mechanism arising from gene overexpression in individuals with the rare 7q11.23 duplication syndrome (Dup7), who have three 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 (two copies) and people with WS (one copy) show standard reactions to painful events. A converging series of human assessments and cross-species cell biological and transcriptomic studies identified one likely candidate in the WS critical region, STX1A, as underlying the pain insensitivity phenotype. STX1A codes for the synaptic vesicle fusion protein Syntaxin1A and neuropeptide release studies from nociceptive DRG neurons, show that excess syntaxin1A compromises exocytosis which when extrapolated to Dup7 individuals, produces a “genetic analgesia” and new potential routes to pain control.