{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:49:49Z","timestamp":1785523789281,"version":"3.56.0"},"reference-count":72,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:00:00Z","timestamp":1714348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["1RM1 GM131981-03"],"award-info":[{"award-number":["1RM1 GM131981-03"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH NRSA postdoctoral fellowship","award":["5F32HL142205"],"award-info":[{"award-number":["5F32HL142205"]}]},{"name":"Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education","award":["2022R1A6A1A03054419"],"award-info":[{"award-number":["2022R1A6A1A03054419"]}]},{"name":"Korean Fund for Regenerative Medicine funded by Ministry of Science and ICT, and Ministry of Health and Welfare","award":["22A0302L1-01"],"award-info":[{"award-number":["22A0302L1-01"]}]},{"name":"NIH","award":["1K99HL153679"],"award-info":[{"award-number":["1K99HL153679"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["20POST35211011"],"award-info":[{"award-number":["20POST35211011"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Translational Research Institute for Space Health (TRISH) through Cooperative Agreement","award":["NNX16AO69A"],"award-info":[{"award-number":["NNX16AO69A"]}]},{"name":"NIH","award":["K99 HL150216"],"award-info":[{"award-number":["K99 HL150216"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["20CDA35260261"],"award-info":[{"award-number":["20CDA35260261"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,5,7]]},"abstract":"<jats:p>\n                    Determining the pathogenicity of hypertrophic cardiomyopathy\u2013associated mutations in the \u03b2-myosin heavy chain (\n                    <jats:italic>MYH7<\/jats:italic>\n                    ) can be challenging due to its variable penetrance and clinical severity. This study investigates the early pathogenic effects of the incomplete-penetrant\n                    <jats:italic>MYH7<\/jats:italic>\n                    G256E mutation on myosin function that may trigger pathogenic adaptations and hypertrophy. We hypothesized that the G256E mutation would alter myosin biomechanical function, leading to changes in cellular functions. We developed a collaborative pipeline to characterize myosin function across protein, myofibril, cell, and tissue levels to determine the multiscale effects on structure\u2013function of the contractile apparatus and its implications for gene regulation and metabolic state. The G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 33%, resulting in more myosin heads available for contraction. Myofibrils from gene-edited\n                    <jats:italic>MYH7<\/jats:italic>\n                    <jats:sup>WT\/G256E<\/jats:sup>\n                    human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster tension development. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. We demonstrated consistent hypercontractile myosin function as a primary consequence of the\n                    <jats:italic>MYH7<\/jats:italic>\n                    G256E mutation across scales, highlighting the pathogenicity of this gene variant. Single-cell transcriptomic and metabolic profiling demonstrated upregulated mitochondrial genes and increased mitochondrial respiration, indicating early bioenergetic alterations. This work highlights the benefit of our multiscale platform to systematically evaluate the pathogenicity of gene variants at the protein and contractile organelle level and their early consequences on cellular and tissue function. We believe this platform can help elucidate the genotype\u2013phenotype relationships underlying other genetic cardiovascular diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2318413121","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T15:17:06Z","timestamp":1714403826000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["Incomplete-penetrant hypertrophic cardiomyopathy\n                    <i>MYH7<\/i>\n                    G256E mutation causes hypercontractility and elevated mitochondrial respiration"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7613-592X","authenticated-orcid":false,"given":"Soah","family":"Lee","sequence":"first","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Department of Biopharmaceutical Convergence, Sungkyunkwan University School of Pharmacy, Suwon, Gyeonggi-do 16419 South Korea"},{"name":"School of Pharmacy, Sungkyunkwan University School of Pharmacy, Suwon, Gyeonggi-do 16419, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison S.","family":"Vander Roest","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheavar A.","family":"Blair","sequence":"additional","affiliation":[{"name":"Biological Engineering, University of California, Santa Barbara, CA 93106"},{"name":"Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7095-4836","authenticated-orcid":false,"given":"Kerry","family":"Kao","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3465-0442","authenticated-orcid":false,"given":"Samantha B.","family":"Bremner","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2440-9612","authenticated-orcid":false,"given":"Matthew C.","family":"Childers","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Pathak","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Heinrich","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Lee","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orlando","family":"Chirikian","sequence":"additional","affiliation":[{"name":"Biological Engineering, University of California, Santa Barbara, CA 93106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0728-9882","authenticated-orcid":false,"given":"Saffie E.","family":"Mohran","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brock","family":"Roberts","sequence":"additional","affiliation":[{"name":"Allen Institute for Cell Science, Seattle, WA 98109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline E.","family":"Smith","sequence":"additional","affiliation":[{"name":"Allen Institute for Cell Science, Seattle, WA 98109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Jahng","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Paik","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6068-8041","authenticated-orcid":false,"given":"Joseph C.","family":"Wu","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruwanthi N.","family":"Gunawardane","sequence":"additional","affiliation":[{"name":"Allen Institute for Cell Science, Seattle, WA 98109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Ruppel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Mack","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4861-2124","authenticated-orcid":false,"given":"Beth L.","family":"Pruitt","sequence":"additional","affiliation":[{"name":"Biological Engineering, University of California, Santa Barbara, CA 93106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5437-9851","authenticated-orcid":false,"given":"Michael","family":"Regnier","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington School of Medicine and College of Engineering, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0000-3821","authenticated-orcid":false,"given":"Sean M.","family":"Wu","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4324-4254","authenticated-orcid":false,"given":"James A.","family":"Spudich","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7761-5853","authenticated-orcid":false,"given":"Daniel","family":"Bernstein","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305"},{"name":"Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60397-3"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.01.019"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311059"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.053575"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.205"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.108.821314"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.010563"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10555-9"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.042339"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax0069"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3408"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1500511"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1802967115"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2025030118"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2018.11.015"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1601959"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2008.09.126"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt119"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.274571"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2016.04.006"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2018.08.008"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad3456"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.10.010"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu205"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab077"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz326"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2020.06.003"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.24.3172"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5262.731"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03401640"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-89451-6"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI4631"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7956"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.89.1.22"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000042675.59901.14"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1039\/C6ME00083E"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.02.026"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2020.108733"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.310363"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2018.03.016"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1177\/20417314221119628"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1018613907574"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1309493110"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1242\/bio.057646"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-004-1363-5"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2010.10.025"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1508073112"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2019.03.001"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-2261-2_6"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600458"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4162"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a004242"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.07.027"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1161\/hh1001.091640"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2012.11.010"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1821660116"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.177683"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.178996"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000021115.24712.99"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.184408"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06639-7"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(02)03009-7"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvv108"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.104.3.317"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002081"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.04.002"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110809"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(00)80027-5"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8551"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-1934-6"},{"key":"e_1_3_5_71_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.112.967026"},{"key":"e_1_3_5_72_2","author":"Lee S.","unstructured":"S. Lee, MYH7 G256E hiPSC-CM (Day 30). NCBI GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE220933. Deposited 14 December 2022.","journal-title":"GEO"}],"updated-by":[{"DOI":"10.1073\/pnas.2410753121","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T00:00:00Z","timestamp":1718582400000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2318413121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T15:11:10Z","timestamp":1718637070000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2318413121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,29]]},"references-count":72,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2024,5,7]]}},"alternative-id":["10.1073\/pnas.2318413121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2318413121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,29]]},"assertion":[{"value":"2023-10-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2318413121"}}