{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:31:07Z","timestamp":1790836267098,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,1,5]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Brugada syndrome is associated with loss-of-function\n              <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n              variants, yet these account for only \u224820% of cases. A recent genome-wide association study identified a novel locus within\n              <jats:italic toggle=\"yes\">MAPRE2<\/jats:italic>\n              , which encodes EB2 (microtubule end-binding protein 2), implicating microtubule involvement in Brugada syndrome.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              A\n              <jats:italic toggle=\"yes\">mapre2<\/jats:italic>\n              knockout zebrafish model was generated using CRISPR\/Cas9 (clustered regularly interspaced short palindromic repeats\/clustered regularly interspaced short palindromic repeat\u2013associated protein 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebrafish line with\n              <jats:italic toggle=\"yes\">cdh2<\/jats:italic>\n              tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with\n              <jats:italic toggle=\"yes\">MAPRE2<\/jats:italic>\n              knockdown and knockout, respectively.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Voltage mapping of\n              <jats:italic toggle=\"yes\">mapre2<\/jats:italic>\n              knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC-CMs. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with\n              <jats:italic toggle=\"yes\">mapre2<\/jats:italic>\n              loss of function, associated with a decrease of detyrosinated tubulin.\n              <jats:italic toggle=\"yes\">MAPRE2<\/jats:italic>\n              knockdown in iPSC-CMs led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of\n              <jats:italic toggle=\"yes\">ttl<\/jats:italic>\n              encoding tubulin tyrosine ligase in\n              <jats:italic toggle=\"yes\">mapre2<\/jats:italic>\n              knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              Genetic ablation of\n              <jats:italic toggle=\"yes\">mapre2<\/jats:italic>\n              led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with\n              <jats:italic toggle=\"yes\">ttl<\/jats:italic>\n              knockdown led to rescue of voltage-gated sodium channel\u2013related functional parameters in\n              <jats:italic toggle=\"yes\">mapre2<\/jats:italic>\n              knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.123.323231","type":"journal-article","created":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T05:00:40Z","timestamp":1702530040000},"page":"46-59","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["The Role of\n            <i>MAPRE2<\/i>\n            and Microtubules in Maintaining Normal Ventricular Conduction"],"prefix":"10.1161","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5883-6383","authenticated-orcid":true,"given":"David Y.","family":"Chiang","sequence":"first","affiliation":[{"name":"Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (D.Y.C., R.V., N.N., A.K., J.R.S., F.V.-O., J.S.O., E.B., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-834X","authenticated-orcid":true,"given":"Arie O.","family":"Verkerk","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Heart Center (A.O.V., C.R.B.), Academic Medical Center, Amsterdam UMC, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachelle","family":"Victorio","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (D.Y.C., R.V., N.N., A.K., J.R.S., F.V.-O., J.S.O., E.B., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris I.","family":"Shneyer","sequence":"additional","affiliation":[{"name":"Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, the Netherlands (B.I.S., B.v.d.V., A.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3534-6880","authenticated-orcid":true,"given":"Babet","family":"van der Vaart","sequence":"additional","affiliation":[{"name":"Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, the Netherlands (B.I.S., B.v.d.V., A.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6576-1922","authenticated-orcid":true,"given":"Mariam","family":"Jouni","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (M.J., D.A.S., P.W.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6356-1433","authenticated-orcid":true,"given":"Nakul","family":"Narendran","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (D.Y.C., R.V., N.N., A.K., J.R.S., F.V.-O., J.S.O., E.B., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8831-5124","authenticated-orcid":true,"given":"Ashmita","family":"Kc","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (D.Y.C., R.V., N.N., A.K., J.R.S., F.V.-O., J.S.O., E.B., C.A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Sampognaro","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (D.Y.C., R.V., N.N., A.K., J.R.S., F.V.-O., J.S.O., E.B., 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