{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T10:35:17Z","timestamp":1762079717550,"version":"3.37.3"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:00:00Z","timestamp":1574726400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:00:00Z","timestamp":1574726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["209583\/Z\/17\/Z"],"award-info":[{"award-number":["209583\/Z\/17\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The sarcolemmal voltage gated sodium channel Na<jats:sub>V<\/jats:sub>1.4 conducts the key depolarizing current that drives the upstroke of the skeletal muscle action potential. It contains four voltage-sensing domains (VSDs) that regulate the opening of the pore domain and ensuing permeation of sodium ions. Mutations that lead to increased Na<jats:sub>V<\/jats:sub>1.4 currents are found in patients with myotonia or hyperkalaemic periodic paralysis (HyperPP). Myotonia is also caused by mutations in the <jats:italic>CLCN1<\/jats:italic>gene that result in loss-of-function of the skeletal muscle chloride channel ClC-1. Mutations affecting arginine residues in the fourth transmembrane helix (S4) of the Na<jats:sub>V<\/jats:sub>1.4 VSDs can result in a leak current through the VSD and hypokalemic periodic paralysis (HypoPP), but these have hitherto not been associated with myotonia. We report a patient with an Nav1.4 S4 arginine mutation, R222Q, presenting with severe myotonia without fulminant paralytic episodes. Other mutations affecting the same residue, R222W and R222G, have been found in patients with HypoPP. We show that R222Q channels have enhanced activation, consistent with myotonia, but also conduct a leak current. The patient carries a concomitant synonymous <jats:italic>CLCN1<\/jats:italic> variant that likely worsens the myotonia and potentially contributes to the amelioration of muscle paralysis. Our data show phenotypic variability for different mutations affecting the same S4 arginine that have implications for clinical therapy.<\/jats:p>","DOI":"10.1038\/s41598-019-54041-0","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T11:03:15Z","timestamp":1574766195000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Myotonia in a patient with a mutation in an S4 arginine residue associated with hypokalaemic periodic paralysis and a concomitant synonymous CLCN1 mutation"],"prefix":"10.1038","volume":"9","author":[{"given":"Michael G.","family":"Thor","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vinojini","family":"Vivekanandam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4338-0686","authenticated-orcid":false,"given":"Marisol","family":"Sampedro-Casta\u00f1eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. Veronica","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Suetterlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richa","family":"Sud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siobhan","family":"Durran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Schorge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitri M.","family":"Kullmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael G.","family":"Hanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8727-9184","authenticated-orcid":false,"given":"Roope","family":"M\u00e4nnikk\u00f6","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,11,26]]},"reference":[{"key":"54041_CR1","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1097\/WCO.0000000000000127","volume":"27","author":"K Suetterlin","year":"2014","unstructured":"Suetterlin, K., Mannikko, R. & Hanna, M. G. Muscle channelopathies: recent advances in genetics, pathophysiology and therapy. Curr Opin Neurol 27, 583\u2013590 (2014).","journal-title":"Curr Opin Neurol"},{"key":"54041_CR2","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/s00424-010-0814-4","volume":"460","author":"K Jurkat-Rott","year":"2010","unstructured":"Jurkat-Rott, K., Holzherr, B., Fauler, M. & Lehmann-Horn, F. Sodium channelopathies of skeletal muscle result from gain or loss of function. Pflugers Arch 460, 239\u2013248 (2010).","journal-title":"Pflugers Arch"},{"key":"54041_CR3","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1007\/164_2017_52","volume":"246","author":"SC Cannon","year":"2018","unstructured":"Cannon, S. C. Sodium Channelopathies of Skeletal Muscle. Handbook of experimental pharmacology 246, 309\u2013330 (2018).","journal-title":"Handbook of experimental pharmacology"},{"key":"54041_CR4","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1002\/cphy.c140062","volume":"5","author":"SC Cannon","year":"2015","unstructured":"Cannon, S. C. Channelopathies of skeletal muscle excitability. Comprehensive Physiology 5, 761\u2013790 (2015).","journal-title":"Comprehensive Physiology"},{"key":"54041_CR5","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.neuron.2013.05.036","volume":"79","author":"JJ Lacroix","year":"2013","unstructured":"Lacroix, J. J., Campos, F. V., Frezza, L. & Bezanilla, F. Molecular bases for the asynchronous activation of sodium and potassium channels required for nerve impulse generation. Neuron 79, 651\u2013657 (2013).","journal-title":"Neuron"},{"key":"54041_CR6","doi-asserted-by":"crossref","unstructured":"Pan, X. et al. Structure of the human voltage-gated sodium channel Nav1.4 in complex with beta1. Science (New York, N.Y.) 362 (2018).","DOI":"10.2210\/pdb6agf\/pdb"},{"key":"54041_CR7","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/0896-6273(95)90078-0","volume":"15","author":"N Yang","year":"1995","unstructured":"Yang, N. & Horn, R. Evidence for voltage-dependent S4 movement in sodium channels. Neuron 15, 213\u2013218 (1995).","journal-title":"Neuron"},{"key":"54041_CR8","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1212\/01.wnl.0000342387.65477.46","volume":"72","author":"E Matthews","year":"2009","unstructured":"Matthews, E. et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 72, 1544\u20131547 (2009).","journal-title":"Neurology"},{"key":"54041_CR9","doi-asserted-by":"publisher","first-page":"112","DOI":"10.3389\/fphar.2012.00112","volume":"3","author":"K Jurkat-Rott","year":"2012","unstructured":"Jurkat-Rott, K., Groome, J. & Lehmann-Horn, F. Pathophysiological role of omega pore current in channelopathies. Front Pharmacol 3, 112 (2012).","journal-title":"Front Pharmacol"},{"key":"54041_CR10","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/nature05598","volume":"446","author":"S Sokolov","year":"2007","unstructured":"Sokolov, S., Scheuer, T. & Catterall, W. A. Gating pore current in an inherited ion channelopathy. Nature 446, 76\u201378 (2007).","journal-title":"Nature"},{"key":"54041_CR11","doi-asserted-by":"publisher","first-page":"1472","DOI":"10.1212\/WNL.0b013e31828cf8d0","volume":"80","author":"A Horga","year":"2013","unstructured":"Horga, A. et al. Prevalence study of genetically defined skeletal muscle channelopathies in England. Neurology 80, 1472\u20131475 (2013).","journal-title":"Neurology"},{"key":"54041_CR12","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1085\/jgp.201010414","volume":"136","author":"S Sokolov","year":"2010","unstructured":"Sokolov, S., Scheuer, T. & Catterall, W. A. Ion permeation and block of the gating pore in the voltage sensor of NaV1.4 channels with hypokalemic periodic paralysis mutations. The Journal of general physiology 136, 225\u2013236 (2010).","journal-title":"The Journal of general physiology"},{"key":"54041_CR13","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1016\/j.neuron.2004.12.047","volume":"45","author":"F Tombola","year":"2005","unstructured":"Tombola, F., Pathak, M. M. & Isacoff, E. Y. Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. Neuron 45, 379\u2013388 (2005).","journal-title":"Neuron"},{"key":"54041_CR14","doi-asserted-by":"publisher","first-page":"4495","DOI":"10.1073\/pnas.1720185115","volume":"115","author":"R Mannikko","year":"2018","unstructured":"Mannikko, R. et al. Spider toxin inhibits gating pore currents underlying periodic paralysis. Proceedings of the National Academy of Sciences of the United States of America 115, 4495\u20134500 (2018).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"54041_CR15","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1002\/mus.25956","volume":"57","author":"SV Tan","year":"2018","unstructured":"Tan, S. V., Z\u2032Graggen, W. J., Hanna, M. G. & Bostock, H. In vivo assessment of muscle membrane properties in the sodium channel myotonias. Muscle & nerve 57, 586\u2013594 (2018).","journal-title":"Muscle & nerve"},{"key":"54041_CR16","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1002\/mus.24069","volume":"49","author":"SV Tan","year":"2014","unstructured":"Tan, S. V. et al. Chloride channels in myotonia congenita assessed by velocity recovery cycles. Muscle & nerve 49, 845\u2013857 (2014).","journal-title":"Muscle & nerve"},{"key":"54041_CR17","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1002\/mus.20928","volume":"37","author":"AF Struyk","year":"2008","unstructured":"Struyk, A. F. & Cannon, S. C. Paradoxical depolarization of BA2+- treated muscle exposed to low extracellular K+: insights into resting potential abnormalities in hypokalemic paralysis. Muscle & nerve 37, 326\u2013337 (2008).","journal-title":"Muscle & nerve"},{"key":"54041_CR18","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1016\/j.nmd.2014.06.439","volume":"24","author":"A Furby","year":"2014","unstructured":"Furby, A. et al. Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia. Neuromuscular disorders: NMD 24, 953\u2013959 (2014).","journal-title":"Neuromuscular disorders: NMD"},{"key":"54041_CR19","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1007\/s10048-017-0525-5","volume":"18","author":"L Maggi","year":"2017","unstructured":"Maggi, L. et al. Coexistence of CLCN1 and SCN4A mutations in one family suffering from myotonia. Neurogenetics 18, 219\u2013225 (2017).","journal-title":"Neurogenetics"},{"key":"54041_CR20","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.jns.2016.08.030","volume":"369","author":"H Kato","year":"2016","unstructured":"Kato, H. et al. A case of non-dystrophic myotonia with concomitant mutations in the SCN4A and CLCN1 genes. Journal of the neurological sciences 369, 254\u2013258 (2016).","journal-title":"Journal of the neurological sciences"},{"key":"54041_CR21","doi-asserted-by":"publisher","first-page":"3766","DOI":"10.1093\/brain\/awt280","volume":"136","author":"F Wu","year":"2013","unstructured":"Wu, F., Mi, W. & Cannon, S. C. Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis. Brain: a journal of neurology 136, 3766\u20133774 (2013).","journal-title":"Brain: a journal of neurology"},{"key":"54041_CR22","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1212\/WNL.0b013e3182886a0e","volume":"80","author":"F Wu","year":"2013","unstructured":"Wu, F., Mi, W. & Cannon, S. C. Bumetanide prevents transient decreases in muscle force in murine hypokalemic periodic paralysis. Neurology 80, 1110\u20131116 (2013).","journal-title":"Neurology"},{"key":"54041_CR23","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1113\/jphysiol.2001.013298","volume":"542","author":"RJG Foppen","year":"2002","unstructured":"Foppen, R. J. G., van Mil, H. G. J. & van Heukelom, J. S. Effects of chloride transport on bistable behaviour of the membrane potential in mouse skeletal muscle. The Journal of physiology 542, 181\u2013191 (2002).","journal-title":"The Journal of physiology"},{"key":"54041_CR24","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1212\/WNL.52.7.1447","volume":"52","author":"LJ Hayward","year":"1999","unstructured":"Hayward, L. J., Sandoval, G. M. & Cannon, S. C. Defective slow inactivation of sodium channels contributes to familial periodic paralysis. Neurology 52, 1447\u20131453 (1999).","journal-title":"Neurology"},{"key":"54041_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-28594-5","volume":"8","author":"L Bayless-Edwards","year":"2018","unstructured":"Bayless-Edwards, L. et al. NaV1.4 DI-S4 periodic paralysis mutation R222W enhances inactivation and promotes leak current to attenuate action potentials and depolarize muscle fibers. Scientific reports 8, 10372 (2018).","journal-title":"Scientific reports"},{"key":"54041_CR26","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1007\/BF00410190","volume":"431","author":"C Chen","year":"1995","unstructured":"Chen, C. & Cannon, S. C. Modulation of Na+ channel inactivation by the beta 1 subunit: a deletion analysis. Pflugers Archiv: European journal of physiology 431, 186\u2013195 (1995).","journal-title":"Pflugers Archiv: European journal of physiology"},{"key":"54041_CR27","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1126\/science.1375395","volume":"256","author":"LL Isom","year":"1992","unstructured":"Isom, L. L. et al. Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel. Science 256, 839\u2013842 (1992).","journal-title":"Science"},{"key":"54041_CR28","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1007\/s00424-008-0600-8","volume":"457","author":"J Webb","year":"2009","unstructured":"Webb, J., Wu, F. F. & Cannon, S. C. Slow inactivation of the NaV1.4 sodium channel in mammalian cells is impeded by co-expression of the beta1 subunit. Pflugers Archiv: European journal of physiology 457, 1253\u20131263 (2009).","journal-title":"Pflugers Archiv: European journal of physiology"},{"key":"54041_CR29","doi-asserted-by":"publisher","first-page":"16586","DOI":"10.1523\/JNEUROSCI.2307-13.2013","volume":"33","author":"Y Yang","year":"2013","unstructured":"Yang, Y. et al. Multistate structural modeling and voltage-clamp analysis of epilepsy\/autism mutation Kv10.2-R327H demonstrate the role of this residue in stabilizing the channel closed state. The Journal of neuroscience 33, 16586\u201316593 (2013).","journal-title":"The Journal of neuroscience"},{"key":"54041_CR30","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1016\/S0896-6273(00)80142-7","volume":"16","author":"SA Seoh","year":"1996","unstructured":"Seoh, S. A., Sigg, D., Papazian, D. M. & Bezanilla, F. Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron 16, 1159\u20131167 (1996).","journal-title":"Neuron"},{"key":"54041_CR31","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1016\/j.cell.2019.06.031","volume":"178","author":"G Wisedchaisri","year":"2019","unstructured":"Wisedchaisri, G. et al. Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel. Cell 178, 993\u20131003 (2019).","journal-title":"Cell"},{"key":"54041_CR32","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/s41586-018-0120-4","volume":"557","author":"D Jiang","year":"2018","unstructured":"Jiang, D. et al. Structural basis for gating pore current in periodic paralysis. Nature 557, 590\u2013594 (2018).","journal-title":"Nature"},{"key":"54041_CR33","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1001\/jama.2012.12607","volume":"308","author":"JM Statland","year":"2012","unstructured":"Statland, J. M. et al. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. Jama 308, 1357\u20131365 (2012).","journal-title":"Jama"},{"key":"54041_CR34","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-27822-2","volume":"8","author":"S Luo","year":"2018","unstructured":"Luo, S. et al. Hypokalaemic periodic paralysis and myotonia in a patient with homozygous mutation p.R1451L in NaV1.4. Scientific reports 8, 9714 (2018).","journal-title":"Scientific reports"},{"key":"54041_CR35","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/mus.21192","volume":"39","author":"W Z\u2032Graggen","year":"2009","unstructured":"Z\u2032Graggen, W. & Bostock, J. H. Velocity recovery cycles of human muscle action potentials and their sensitivity to ischemia. Muscle & nerve 39, 616\u2013626 (2009).","journal-title":"Muscle & nerve"},{"key":"54041_CR36","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1002\/mus.23293","volume":"46","author":"SV Tan","year":"2012","unstructured":"Tan, S. V. et al. Membrane dysfunction in Andersen-Tawil syndrome assessed by velocity recovery cycles. Muscle & nerve 46, 193\u2013203 (2012).","journal-title":"Muscle & nerve"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-54041-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-54041-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-54041-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T16:30:37Z","timestamp":1671294637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-54041-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,26]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["54041"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-54041-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2019,11,26]]},"assertion":[{"value":"18 June 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 November 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17560"}}