{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSCN9A encodes the pore‐forming α‐subunit of the voltage‐gated sodium channel Nav1.7, a molecular “gatekeeper” that amplifies small subthreshold depolarizations in peripheral nociceptive and sympathetic neurons. In both humans and animal models, Nav1.7 plays an essential, nonredundant role in pain detection—its normal channel activity is required to allow neuronal firing in response to noxious stimuli, and structural studies have begun to delineate the atomic basis of its gating properties. Moreover, naturally occurring variants—including specific coding single nucleotide polymorphisms that subtly alter channel biophysics—are shown to modulate patients’ pain thresholds."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic alterations in SCN9A can lead to dramatic, clinically recognizable phenotypes. Loss‐of‐function mutations result in congenital insensitivity to pain (often accompanied by anosmia), owing to a complete abrogation of Nav1.7 activity in nociceptive neurons. In contrast, gain‐of‐function mutations—with shifts in activation to more hyperpolarized potentials, impaired inactivation, or enhanced persistent and ramp currents—render sensory neurons hyperexcitable and underlie several painful neuropathies, such as primary erythermalgia (erythromelalgia), paroxysmal extreme pain disorder, and painful small fiber neuropathy. Additionally, some SCN9A variants may subtly predispose individuals to heightened pain responses or even contribute to other neurological phenotypes such as febrile seizures, thereby highlighting the spectrum of channelopathies linked to Nav1.7 dysfunction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdvanced biophysical investigations and translational studies have further illuminated Nav1.7 as a prime therapeutic target. High‐resolution structural analyses and electrophysiological studies using mutant channels have provided insight into altered gating mechanisms that underlie hyperexcitability, while pharmacological studies—including those using selective peptides from centipede venom and analyses of local anesthetic efficacy—demonstrate that targeting Nav1.7 could yield potent analgesia. In addition, aberrant Nav1.7 expression has been implicated in non‐pain conditions such as cancer metastasis, and emerging data indicate that Nav1.7 activity can influence gene expression pathways (for example, opioid peptide regulation), thereby expanding its potential impact on neuronal signaling. Finally, intricate mechanisms regulating Nav1.7 trafficking—including post‐translational modifications via SUMOylation—highlight additional layers of functional control that may be exploited for improved pain therapeutics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "James J Cox, Frank Reimann, Adeline K Nicholas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An SCN9A channelopathy causes congenital inability to experience pain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature05413"}], "href": "https://doi.org/10.1038/nature05413"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17167479"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17167479"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sulayman D Dib-Hajj, Yang Yang, Joel A Black, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Na(V)1.7 sodium channel: from molecule to man."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Rev Neurosci (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nrn3404"}], "href": "https://doi.org/10.1038/nrn3404"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23232607"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23232607"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Joost P H Drenth, Stephen G Waxman "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI33297"}], "href": "https://doi.org/10.1172/JCI33297"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18060017"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18060017"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Frank Reimann, James J Cox, Inna Belfer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pain perception is altered by a nucleotide polymorphism in SCN9A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0913181107"}], "href": "https://doi.org/10.1073/pnas.0913181107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20212137"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20212137"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jan Weiss, Martina Pyrski, Eric Jacobi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss-of-function mutations in sodium channel Nav1.7 cause anosmia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature09975"}], "href": "https://doi.org/10.1038/nature09975"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21441906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21441906"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Y Yang, Y Wang, S Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2003.012153"}], "href": "https://doi.org/10.1136/jmg.2003.012153"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14985375"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14985375"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Catharina G Faber, Janneke G J Hoeijmakers, Hye-Sook Ahn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Neurol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ana.22485"}], "href": "https://doi.org/10.1002/ana.22485"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21698661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21698661"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Y P Goldberg, J MacFarlane, M L MacDonald, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1399-0004.2007.00790.x"}], "href": "https://doi.org/10.1111/j.1399-0004.2007.00790.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17470132"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17470132"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Theodore R Cummins, Sulayman D Dib-Hajj, Stephen G Waxman "}, {"type": "b", "children": [{"type": "t", "text": "Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.2695-04.2004"}], "href": "https://doi.org/10.1523/JNEUROSCI.2695-04.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15385606"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15385606"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Sulayman D Dib-Hajj, Theodore R Cummins, Joel A Black, et al. "}, {"type": "b", "children": [{"type": "t", "text": "From genes to pain: Na v 1.7 and human pain disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Trends Neurosci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tins.2007.08.004"}], "href": "https://doi.org/10.1016/j.tins.2007.08.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17950472"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17950472"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Nanda A Singh, Chris Pappas, E Jill Dahle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1000649"}], "href": "https://doi.org/10.1371/journal.pgen.1000649"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19763161"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19763161"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Sultan Ahmad, Leif Dahllund, Anders B Eriksson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A stop codon mutation in SCN9A causes lack of pain sensation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddm160"}], "href": "https://doi.org/10.1093/hmg/ddm160"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17597096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17597096"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Chongyang Han, Anthony M Rush, Sulayman D Dib-Hajj, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Neurol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ana.20776"}], "href": "https://doi.org/10.1002/ana.20776"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16392115"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16392115"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Patrick L Sheets, James O Jackson, Stephen G Waxman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Physiol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1113/jphysiol.2006.127027"}], "href": "https://doi.org/10.1113/jphysiol.2006.127027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17430993"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17430993"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Joost P H Drenth, Rene H M te Morsche, Gerard Guillet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.0022-202X.2005.23737.x"}], "href": "https://doi.org/10.1111/j.0022-202X.2005.23737.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15955112"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15955112"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "M Estacion, S D Dib-Hajj, P J Benke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.3443-08.2008"}], "href": "https://doi.org/10.1523/JNEUROSCI.3443-08.2008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18945915"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18945915"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Huaizong Shen, Dongliang Liu, Kun Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structures of human Na"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "v"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": "1.7 channel in complex with auxiliary subunits and animal toxins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.aaw2493"}], "href": "https://doi.org/10.1126/science.aaw2493"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30765606"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30765606"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Shilong Yang, Yao Xiao, Di Kang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1306285110"}], "href": "https://doi.org/10.1073/pnas.1306285110"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24082113"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24082113"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Michael S Minett, Vanessa Pereira, Shafaq Sikandar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms9967"}], "href": "https://doi.org/10.1038/ncomms9967"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26634308"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26634308"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Lucy A McDermott, Greg A Weir, Andreas C Themistocleous, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defining the Functional Role of Na"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "V"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": "1.7 in Human Nociception."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2019.01.047"}], "href": "https://doi.org/10.1016/j.neuron.2019.01.047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30795902"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30795902"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "J K J Diss, D Stewart, F Pani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A potential novel marker for human prostate cancer: voltage-gated sodium channel expression in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prostate Cancer Prostatic Dis (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.pcan.4500796"}], "href": "https://doi.org/10.1038/sj.pcan.4500796"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16088330"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16088330"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "T Patrick Harty, Sulayman D Dib-Hajj, Lynda Tyrrell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.3424-06.2006"}], "href": "https://doi.org/10.1523/JNEUROSCI.3424-06.2006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17135418"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17135418"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Tanya Z Fischer, Elaine S Gilmore, Mark Estacion, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Neurol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ana.21678"}], "href": "https://doi.org/10.1002/ana.21678"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19557861"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19557861"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Brian W Jarecki, Andrew D Piekarz, James O Jackson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI40801"}], "href": "https://doi.org/10.1172/JCI40801"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20038812"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20038812"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Jonathan W Theile, Brian W Jarecki, Andrew D Piekarz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navbeta4 peptide-mediated resurgent sodium currents."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Physiol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1113/jphysiol.2010.200915"}], "href": "https://doi.org/10.1113/jphysiol.2010.200915"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21115638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21115638"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Sulayman D Dib-Hajj, Mark Estacion, Brian W Jarecki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Paroxysmal extreme pain disorder M1627K mutation in human Nav1.7 renders DRG neurons hyperexcitable."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pain (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1744-8069-4-37"}], "href": "https://doi.org/10.1186/1744-8069-4-37"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18803825"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18803825"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Iulia Blesneac, Andreas C Themistocleous, Carl Fratter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pain (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/j.pain.0000000000001116"}], "href": "https://doi.org/10.1097/j.pain.0000000000001116"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29176367"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29176367"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Erik T Dustrude, Aubin Moutal, Xiaofang Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hierarchical CRMP2 posttranslational modifications control NaV1.7 function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1610531113"}], "href": "https://doi.org/10.1073/pnas.1610531113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27940916"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27940916"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Erik T Dustrude, Sarah M Wilson, Weina Ju, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.474924"}], "href": "https://doi.org/10.1074/jbc.M113.474924"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23836888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23836888"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Xiaoyang Cheng, Sulayman D Dib-Hajj, Lynda Tyrrell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation I136V alters electrophysiological properties of the Na(v)1.7 channel in a family with onset of erythromelalgia in the second decade."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pain (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1744-8069-4-1"}], "href": "https://doi.org/10.1186/1744-8069-4-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18171466"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18171466"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Yang Yang, Sulayman D Dib-Hajj, Jian Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Na(V)1.7 mutant channel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms2184"}], "href": "https://doi.org/10.1038/ncomms2184"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23149731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23149731"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Gilberto Vargas-Alarcon, Edith Alvarez-Leon, Jose-Manuel Fragoso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Musculoskelet Disord (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2474-13-23"}], "href": "https://doi.org/10.1186/1471-2474-13-23"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22348792"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22348792"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Tanya Z Fischer, Stephen G Waxman "}, {"type": "b", "children": [{"type": "t", "text": "Familial pain syndromes from mutations of the NaV1.7 sodium channel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann N Y Acad Sci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1749-6632.2009.05110.x"}], "href": "https://doi.org/10.1111/j.1749-6632.2009.05110.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20146699"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20146699"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Janneke G J Hoeijmakers, Chongyang Han, Ingemar S J Merkies, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Small nerve fibres, small hands and small feet: a new syndrome of pain, dysautonomia and acromesomelia in a kindred with a novel NaV1.7 mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awr349"}], "href": "https://doi.org/10.1093/brain/awr349"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22286749"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22286749"}]}]}]}