{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:50:42Z","timestamp":1788385842392,"version":"build-2803163510"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T00:00:00Z","timestamp":1626220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Charcot neuroarthropathy is a systemic disease with pathological changes in the musculoskeletal system, which leads to fractures, dislocations, and deformities involving multiple bones and joints, particularly those of the feet. While the common underlying cause of Charcot neuroarthropathy is diabetes mellitus, it is also associated with congenital insensitivity to pain (CIP). CIP is a rare disorder caused by loss-of-function mutations in <jats:italic>SCN9A<\/jats:italic> encoding Nav1.7. In this study, we report a patient with CIP from a consanguineous family susceptible to Charcot neuroarthropathy with a novel <jats:italic>SCN9A<\/jats:italic> mutation. This report involves the case of a middle-aged man who suffered from CIP, had repeated painless fractures, and developed bone and joint destruction. The physical and radiological examinations revealed that multiple joints were swollen and deformed, and soft-tissue trauma was evident. We identified a novel homozygous <jats:italic>SCN9A<\/jats:italic> mutation (p.Cys1339Arg) by whole-exome sequencing (WES), which was verified using Sanger sequencing. In addition, the wild-type (WT) and mutated p. Cys1339Arg were assessed in HEK293 cells expressing Nav1.7, and the results showed that p. Cys1339Arg almost abolished the Nav1.7 sodium current. In conclusion, Charcot neuroarthropathy associated with CIP demonstrated a wider spectrum of Charcot neuroarthropathy than was previously recognized or documented. In addition, this finding is conducive to understanding the critical amino acids for maintaining the function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.<\/jats:p>","DOI":"10.3389\/fnins.2021.697167","type":"journal-article","created":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T20:43:37Z","timestamp":1626295417000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Case Report: Mutant SCN9A Susceptible to Charcot Neuroarthropathy in a Patient With Congenital Insensitivity to Pain"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiao-hui","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-guang","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong-hua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shui-jiao","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuang-zhuang","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-qiao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-ping","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1007\/s00424-020-02419-9","article-title":"Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels.","volume":"472","author":"Baker","year":"2020","journal-title":"Pflugers Archiv"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1510","DOI":"10.1001\/jamaneurol.2015.2347","article-title":"The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review.","volume":"72","author":"Callaghan","year":"2015","journal-title":"JAMA Neurol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/j.spinee.2007.04.005","article-title":"Charcot arthropathy because of congenital insensitivity to pain in an adult.","volume":"8","author":"Cassidy","year":"2008","journal-title":"Spine J."},{"key":"B4","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0896-6273(00)81133-2","article-title":"From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.","volume":"26","author":"Catterall","year":"2000","journal-title":"Neuron"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2495","DOI":"10.1007\/s11064-017-2314-9","article-title":"Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy.","volume":"42","author":"Catterall","year":"2017","journal-title":"Neurochem. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1038\/nature05413","article-title":"An SCN9A channelopathy causes congenital inability to experience pain.","volume":"444","author":"Cox","year":"2006","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"696","DOI":"10.2106\/jbjs.17.00785","article-title":"Charcot Neuroarthropathy of the Foot and Ankle.","volume":"100","author":"Dodd","year":"2018","journal-title":"J. Bone Joint Surg. Am."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1177\/1744806919881846","article-title":"Rat Na1.7 loss-of-function genetic model: Deficient nociceptive and neuropathic pain behavior with retained olfactory function and intra-epidermal nerve fibers.","volume":"15","author":"Grubinska","year":"2019","journal-title":"Mole. Pain"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00271","article-title":"Human Dorsal Root Ganglia.","volume":"13","author":"Haberberger","year":"2019","journal-title":"Front. Cell Neurosci."},{"key":"B10","first-page":"1009","article-title":"Nervous arthropathies.","volume":"138","author":"Hubault","year":"1982","journal-title":"Rev. Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1136\/jnnp-2012-303719","article-title":"Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia.","volume":"84","author":"Klein","year":"2013","journal-title":"J. Neurol. Neurosurg. Psychiatry."},{"key":"B12","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1002\/j.1460-2075.1995.tb07091.x","article-title":"Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells.","volume":"14","author":"Klugbauer","year":"1995","journal-title":"EMBO J."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1186\/1757-1146-5-26","article-title":"Diabetic foot disease in the United Kingdom: about time to put feet first.","volume":"5","author":"McInnes","year":"2012","journal-title":"J. Foot Ankle Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"12706","DOI":"10.1073\/pnas.0404915101","article-title":"Nociceptor-specific gene deletion reveals a major role for Na(v)1.7 (PN1) in acute and inflammatory pain.","volume":"101","author":"Nassar","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"8245","DOI":"10.1073\/pnas.0602813103","article-title":"A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons.","volume":"103","author":"Rush","year":"2006","journal-title":"PNAS"},{"key":"B16","doi-asserted-by":"publisher","first-page":"10180","DOI":"10.1523\/jneurosci.1049-18.2018","article-title":"Insensitivity to Pain upon Adult-Onset Deletion of Nav1.7 or Its Blockade with Selective Inhibitors.","volume":"38","author":"Shields","year":"2018","journal-title":"J. Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.pediatrneurol.2013.09.007","article-title":"A novel mutation in SCN9A in a child with congenital insensitivity to pain.","volume":"50","author":"Shorer","year":"2014","journal-title":"Pediatr. Neurol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1073\/pnas.94.4.1527","article-title":"Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons.","volume":"94","author":"Toledo-Aral","year":"1997","journal-title":"Neurbiology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1302\/0301-620X.98B9","article-title":"The Charcot foot Pathophysiology, Diagnosis and Classification.","volume":"98","author":"Watts","year":"2016","journal-title":"Bone Joint J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1016\/s1474-4422(14)70150-4","article-title":"Sodium channel genes in pain-related disorders: phenotype\u2013genotype associations and recommendations for clinical use.","volume":"13","author":"Waxman","year":"2014","journal-title":"Lancet Neurol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1001\/archneurol.2012.21","article-title":"Link Between Pain and Olfaction in an Inherited Sodium Channelopathy.","volume":"69","author":"Zufall","year":"2012","journal-title":"Archiv. Neurol."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.697167\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T20:43:41Z","timestamp":1626295421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.697167\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,14]]},"references-count":21,"alternative-id":["10.3389\/fnins.2021.697167"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2021.697167","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,14]]},"article-number":"697167"}}