{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T03:55:01Z","timestamp":1771559701818,"version":"3.50.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Broad Institute of MIT and Harvard Center for Mendelian Genomics"},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung and Blood Institute","doi-asserted-by":"crossref","award":["UM1 HG008900"],"award-info":[{"award-number":["UM1 HG008900"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["R01 HG009141"],"award-info":[{"award-number":["R01 HG009141"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Australian National Health and Medical Research Council"},{"name":"Career Development Fellowship","award":["APP1162503"],"award-info":[{"award-number":["APP1162503"]}]},{"name":"Early Career Fellowship","award":["APP1139961"],"award-info":[{"award-number":["APP1139961"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Erythromelalgia (EM), is a familial pain syndrome characterized by episodic \u2018burning\u2019 pain, warmth, and erythema. EM is caused by monoallelic variants in SCN9A, which encodes the voltage-gated sodium channel (NaV) NaV1.7. Over 25 different SCN9A mutations attributed to EM have been described to date, all identified in the SCN9A transcript utilizing exon 6N. Here we report a novel SCN9A missense variant identified in seven related individuals with stereotypic episodes of bilateral lower limb pain presenting in childhood. The variant, XM_011511617.3:c.659G&amp;gt;C;p.(Arg220Pro), resides in the exon 6A of SCN9A, an exon previously shown to be selectively incorporated by developmentally regulated alternative splicing. The mutation is located in the voltage-sensing S4 segment of domain I, which is important for regulating channel activation. Functional analysis showed the p.Arg220Pro mutation altered voltage-dependent activation and delayed channel inactivation, consistent with a NaV1.7 gain-of-function molecular phenotype. These results demonstrate that alternatively spliced isoforms of SCN9A should be included in all genomic testing of EM.<\/jats:p>","DOI":"10.1093\/hmg\/ddad152","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T14:35:03Z","timestamp":1695047703000},"page":"103-109","source":"Crossref","is-referenced-by-count":4,"title":["Erythromelalgia caused by the missense mutation p.Arg220Pro in an alternatively spliced exon of <i>SCN9A<\/i> (NaV1.7)"],"prefix":"10.1093","volume":"33","author":[{"given":"Jennifer R","family":"Deuis","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience , 306 Carmody Road, , St Lucia, QLD 4072 , Australia"},{"name":"The University of Queensland , 306 Carmody Road, , St Lucia, QLD 4072 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Smitha","family":"Kumble","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute, 50 Flemington Road, Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"},{"name":"Department of Paediatrics, The University of Melbourne , 50 Flemington Road, Parkville, VIC 3052 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Keramidas","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience , 306 Carmody Road, , St Lucia, QLD 4072 , Australia"},{"name":"The University of Queensland , 306 Carmody Road, , St Lucia, QLD 4072 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lotten","family":"Ragnarsson","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience , 306 Carmody Road, , St Lucia, QLD 4072 , Australia"},{"name":"The University of Queensland , 306 Carmody Road, , St Lucia, QLD 4072 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cas","family":"Simons","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute, 50 Flemington Road, Royal Children\u2019s Hospital , Parkville, VIC 3052 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn","family":"Pais","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, MA 02142 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan M","family":"White","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, The University of Melbourne , 50 Flemington Road, Parkville, VIC 3052 , Australia"},{"name":"Victorian Clinical Genetics Services, Royal Children's Hospital , 50 Flemington Road, Parkville, VIC 3052 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Vetter","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience , 306 Carmody Road, , St Lucia, QLD 4072 , Australia"},{"name":"The University of Queensland , 306 Carmody Road, , St Lucia, QLD 4072 , Australia"},{"name":"School of Pharmacy, 20 Cornwall Street, The University of Queensland , Woolloongabba, QLD 4102 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"2024012011291380400_ref1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s13023-015-0347-1","article-title":"Primary erythromelalgia: a review","volume":"10","author":"Tang","year":"2015","journal-title":"Orphanet J Rare Dis"},{"key":"2024012011291380400_ref2","doi-asserted-by":"crossref","first-page":"e0152405","DOI":"10.1371\/journal.pone.0152405","article-title":"Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release","volume":"11","author":"Alexandrou","year":"2016","journal-title":"PLoS One"},{"key":"2024012011291380400_ref3","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/ncomms1795","article-title":"Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons","volume":"3","author":"Minett","year":"2012","journal-title":"Nat Commun"},{"key":"2024012011291380400_ref4","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.pharmthera.2016.11.015","article-title":"NaV1.7 as a pain target\u2014from gene to pharmacology","volume":"172","author":"Vetter","year":"2017","journal-title":"Pharmacol Ther"},{"key":"2024012011291380400_ref5","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1124\/pr.57.4.4","article-title":"International Union of Pharmacology. 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