Abstract
SummaryLoss-of-function mutations in NaV1.7 cause congenital insensitivity to pain (CIP); this voltage-gated sodium channel is therefore a key target for analgesic drug development. Utilizing a multi-modal approach, we investigated how NaV1.7 mutations lead to human pain insensitivity. Skin biopsy and microneurography revealed an absence of C-fiber nociceptors in CIP patients, reflected in a reduced cortical response to capsaicin on fMRI. Epitope tagging of endogenous NaV1.7 revealed the channel to be localized at the soma membrane, axon, axon terminals, and the nodes of Ranvier of induced pluripotent stem cell (iPSC) nociceptors. CIP patient-derived iPSC nociceptors exhibited an inability to properly respond to depolarizing stimuli, demonstrating that NaV1.7 is a key regulator of excitability. Using this iPSC nociceptor platform, we found that some NaV1.7 blockers undergoing clinical trials lack specificity. CIP, therefore, arises due to a profound loss of functional nociceptors, which is more pronounced than that reported in rodent models, or likely achievable following acute pharmacological blockade.Video
Highlights
Bi-allelic inactivating mutations in SCN9A, which encodes the voltage-gated sodium channel (VGSC) NaV1.7, result in the striking clinical phenotype of congenital insensitivity to pain (CIP) (Cox et al, 2006; Goldberg et al, 2007)
Quantitative sensory testing (QST) confirmed the insensitivity to pain phenotype as neither noxious temperature nor noxious mechanical stimuli were felt as painful (Figure 1A)
To study the function of NaV1.7 independent of inter-patient genetic variability, we introduced a homozygous SCN9A frameshift mutation (N842X) into a healthy control induced pluripotent stem cell (iPSC) line (HC1), generating a NaV1.7 knockout (NaV1.7 KO) (Figure S4B)
Summary
Bi-allelic inactivating mutations in SCN9A, which encodes the voltage-gated sodium channel (VGSC) NaV1.7, result in the striking clinical phenotype of congenital insensitivity to pain (CIP) (Cox et al, 2006; Goldberg et al, 2007). These individuals do not perceive pain in response to noxious stimuli (Bennett and Woods, 2014), be it mechanical, thermal, or chemical in form. The only other clinical feature of bi-allelic loss-of-function (LOF) NaV1.7 mutations is anosmia (Weiss et al, 2011). These findings have led to extensive interest in selectively targeting NaV1.7 as a means to develop novel analgesics
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
