{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:58Z","timestamp":1792790398482,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,14]]},"group-title":"Genetics","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Riley Children's Foundation","award":["25-A23"],"award-info":[{"award-number":["25-A23"]}],"id":[{"id":"https:\/\/ror.org\/03sabpy05","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes of Health","award":["U01NS139219"],"award-info":[{"award-number":["U01NS139219"]}]},{"award":["R01AR078189"],"award-info":[{"award-number":["R01AR078189"]}],"id":[{"id":"https:\/\/ror.org\/006zn3t30","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Hypokalemic periodic paralysis (HypoPP) is an inherited skeletal muscle ion channelopathy of\n                  <jats:italic>CACNA1S<\/jats:italic>\n                  or\n                  <jats:italic>SCN4A<\/jats:italic>\n                  characterized by recurrent episodes of weakness, often triggered by rest after exercise or by reduced K+ (carbohydrate ingestion, stress). Here, we describe a multigenerational family in whom a\n                  <jats:italic>KCNA7<\/jats:italic>\n                  missense variant [c.834A&gt;C (p.Arg278Ser)] co-segregated with susceptibility to recurrent attacks of weakness in association with hypokalemia as low as 1.3 mEq\/L and a 40% decrement of the compound muscle action potential after exercise, suggesting an additional HypoPP gene. Arg278 is the outermost positively charged residue (R1) within the S4 transmembrane segment of the voltage-sensor domain of K\n                  <jats:sub>V<\/jats:sub>\n                  1.7, orthologous to the canonical patten of arginine missense mutations at R1 or R2 in S4 segments for HypoPP-mutant Ca\n                  <jats:sub>V<\/jats:sub>\n                  1.1 and Na\n                  <jats:sub>V<\/jats:sub>\n                  1.4 channels. To determine the functional consequences of Arg278Ser, we expressed wild-type and mutant K\n                  <jats:sub>V<\/jats:sub>\n                  1.7 channels in\n                  <jats:italic>Xenopus<\/jats:italic>\n                  oocytes and HEK293 cells. Arg278Ser, but not wild-type K\n                  <jats:sub>V<\/jats:sub>\n                  1.7, generated an anomalous inwardly rectifying current at hyperpolarized membrane potentials that was nonselective Na\n                  <jats:sup>+<\/jats:sup>\n                  or K\n                  <jats:sup>+<\/jats:sup>\n                  , consistent with the anomalous gating pore conductance that causes susceptibility to HypoPP. Other pathogenic variants of\n                  <jats:italic>KCNA7<\/jats:italic>\n                  have previously been implicated only in inherited cardiac arrhythmias. Collectively, the genetic, structural and electrophysiological findings support\n                  <jats:italic>KCNA7<\/jats:italic>\n                  Arg278Ser as a pathogenic variant underlying HypoPP and implicate\n                  <jats:italic>KCNA7<\/jats:italic>\n                  as a disease gene for periodic paralysis, extending the established gating-pore mechanism of HypoPP to K\n                  <jats:sub>V<\/jats:sub>\n                  1.7.\n                <\/jats:p>","DOI":"10.64898\/2026.09.09.750381","type":"posted-content","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:45:12Z","timestamp":1789447512000},"source":"Crossref","is-referenced-by-count":0,"title":["A New Disease Gene for Hypokalemic Periodic Paralysis,\n                  <i>KCNA7<\/i>\n                  , Established in a Multigenerational Family"],"prefix":"10.64898","author":[{"given":"Khurram","family":"Liaqat","sequence":"first","affiliation":[{"name":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gourav","family":"Saha","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Samueli School of Engineering, University of California at Los Angeles, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Guo","sequence":"additional","affiliation":[{"name":"Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla","family":"Treat","sequence":"additional","affiliation":[{"name":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenfen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Summan","family":"Thahiem","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Undiagnosed Disease Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C","family":"Kincaid","sequence":"additional","affiliation":[{"name":"Department of Neurology, Indiana University, Indianapolis, IN 46202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rubart-von der Lohe","sequence":"additional","affiliation":[{"name":"Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Vetrini","sequence":"additional","affiliation":[{"name":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Cannon","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Samueli School of Engineering, University of California at Los Angeles, USA"},{"name":"Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles, USA"},{"name":"Department of Neurology, David Geffen School of Medicine, University of California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Conboy","sequence":"additional","affiliation":[{"name":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, 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