{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T10:31:55Z","timestamp":1781951515549,"version":"3.54.5"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,5,21]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Many cardiomyopathy\u2010associated\n              <jats:italic>FLNC<\/jats:italic>\n              pathogenic variants are heterozygous truncations, and\n              <jats:italic>FLNC<\/jats:italic>\n              pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We describe an individual with biallelic\n              <jats:italic>FLNC<\/jats:italic>\n              pathogenic variants, p.Arg650X and c.970\u20104A&gt;G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with\n              <jats:italic>FLNC<\/jats:italic>\n              variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970\u20104A&gt;G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell\u2010derived cardiomyocytes (iPSC\u2010CMs) were generated. The\n              <jats:italic>FLNC<\/jats:italic>\n              truncation, Arg650X\/c.970\u20104A&gt;G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous\n              <jats:italic>FLNC<\/jats:italic>\n              disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC\u2010CMs for response to the proteasome inhibitor bortezomib. After exposure to low\u2010dose bortezomib,\n              <jats:italic>FLNC\u2010<\/jats:italic>\n              null iPSC\u2010CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I\/II.\n              <jats:italic>FLNC<\/jats:italic>\n              null iPSC\u2010CMs had prolonged electric field potential, which was further prolonged in the presence of low\u2010dose bortezomib.\n              <jats:italic>FLNC<\/jats:italic>\n              null engineered heart tissues had impaired function after low\u2010dose bortezomib.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              <jats:italic>FLNC<\/jats:italic>\n              pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC\u2010CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib\u2010induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.123.030467","type":"journal-article","created":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T10:28:47Z","timestamp":1716028127000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Reduction of Filamin C Results in Altered Proteostasis, Cardiomyopathy, and Arrhythmias"],"prefix":"10.1161","volume":"13","author":[{"given":"Joyce C.","family":"Ohiri","sequence":"first","affiliation":[{"name":"Center for Genetic Medicine, Feinberg School of Medicine Northwestern University Chicago IL 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4039-8490","authenticated-orcid":false,"given":"Lubna","family":"Choudhury","sequence":"additional","affiliation":[{"name":"Bluhm Cardiovascular Institute Northwestern Medicine Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6166-640X","authenticated-orcid":false,"given":"David Y.","family":"Barefield","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine, Feinberg School of Medicine Northwestern University Chicago IL USA"},{"name":"Cell and Molecular Physiology Loyola University Stritch School of Medicine Maywood IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7627-7119","authenticated-orcid":false,"given":"Dominic","family":"Fullenkamp","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine, Feinberg School of Medicine 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