{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:20:12Z","timestamp":1791498012181,"version":"4.3.4"},"reference-count":92,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,4,12]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K\n              <jats:sup>+<\/jats:sup>\n              channel Kir2.1. The extracellular Cys (cysteine)\n              <jats:sub>122<\/jats:sub>\n              -to-Cys\n              <jats:sub>154<\/jats:sub>\n              disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys\n              <jats:sub>122<\/jats:sub>\n              -to-Cys\n              <jats:sub>154<\/jats:sub>\n              disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We identified a Kir2.1 loss-of-function mutation (c.366 A&gt;T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1\n              <jats:sup>C122Y<\/jats:sup>\n              variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Kir2.1\n              <jats:sup>C122Y<\/jats:sup>\n              mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1\n              <jats:sup>C122Y<\/jats:sup>\n              cardiomyocytes showed significantly reduced inwardly rectifier K+ (I\n              <jats:sub>K1<\/jats:sub>\n              ) and inward Na+ (I\n              <jats:sub>Na<\/jats:sub>\n              ) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate\u2013binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1\n              <jats:sup>C122Y<\/jats:sup>\n              mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and Na\n              <jats:sub>V<\/jats:sub>\n              1.5 proteins.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              The extracellular Cys\n              <jats:sub>122<\/jats:sub>\n              -to-Cys\n              <jats:sub>154<\/jats:sub>\n              disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate\u2013dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the Na\n              <jats:sub>V<\/jats:sub>\n              1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.123.323895","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T05:00:30Z","timestamp":1710738030000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Extracellular Kir2.1\n            <sup>C122Y<\/sup>\n            Mutant Upsets Kir2.1-PIP\n            <sub>2<\/sub>\n            Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome"],"prefix":"10.1161","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5330-8613","authenticated-orcid":true,"given":"Francisco M.","family":"Cruz","sequence":"first","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (F.M.C., A.M., A.I.M.-M., L.K.G., M.L.V.-P., I.M.-C., P.S.P., J.M.R.R., F.J.B.-J., F.M.d.B., J.A.B., J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9952-6947","authenticated-orcid":true,"given":"\u00c1lvaro","family":"Mac\u00edas","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (F.M.C., A.M., A.I.M.-M., L.K.G., M.L.V.-P., I.M.-C., P.S.P., J.M.R.R., F.J.B.-J., F.M.d.B., J.A.B., J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5011-2786","authenticated-orcid":true,"given":"Ana I.","family":"Moreno-Manuel","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (F.M.C., A.M., A.I.M.-M., L.K.G., M.L.V.-P., I.M.-C., P.S.P., J.M.R.R., F.J.B.-J., F.M.d.B., J.A.B., J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian K.","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (F.M.C., A.M., A.I.M.-M., L.K.G., M.L.V.-P., I.M.-C., P.S.P., J.M.R.R., F.J.B.-J., F.M.d.B., J.A.B., J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Linarejos","family":"Vera-Pedrosa","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (F.M.C., A.M., A.I.M.-M., L.K.G., M.L.V.-P., I.M.-C., P.S.P., J.M.R.R., F.J.B.-J., F.M.d.B., J.A.B., J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Mart\u00ednez-Carrascoso","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (F.M.C., A.M., A.I.M.-M., L.K.G., M.L.V.-P., I.M.-C., P.S.P., J.M.R.R., F.J.B.-J., F.M.d.B., J.A.B., J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"S\u00e1nchez P\u00e9rez","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (F.M.C., A.M., A.I.M.-M., L.K.G., M.L.V.-P., I.M.-C., P.S.P., J.M.R.R., F.J.B.-J., F.M.d.B., J.A.B., J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0566-9315","authenticated-orcid":true,"given":"Juan Manuel","family":"Ruiz Robles","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (F.M.C., A.M., A.I.M.-M., L.K.G., M.L.V.-P., I.M.-C., P.S.P., J.M.R.R., F.J.B.-J., F.M.d.B., J.A.B., J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0325-7349","authenticated-orcid":true,"given":"Francisco J.","family":"Berm\u00fadez-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Centro Nacional 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