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

TL;DR

People with a rare genetic duplication are insensitive to pain due to overexpression of the STX1A gene, which disrupts pain signaling in nerve cells.

Contribution

This study identifies STX1A overexpression as a novel mechanism of pain insensitivity in 7q11.23 duplication syndrome.

Findings

Individuals with Dup7 show pain insensitivity despite serious injuries.

STX1A overexpression impairs neuropeptide exocytosis in nociceptive neurons.

Excess syntaxin1A leads to a 'genetic analgesia' mechanism in Dup7.

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.

<p>Overexpression of syntaxin1A in individuals with 7q11.23 duplication syndrome produces insensitivity to a broad spectrum of painful injuries.</p>

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