{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T16:32:38Z","timestamp":1789835558926,"version":"4.0.1"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"24","license":[{"start":{"date-parts":[[2016,5,31]],"date-time":"2016-05-31T00:00:00Z","timestamp":1464652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.pnas.org\/preview_site\/misc\/userlicense.xhtml"}],"funder":[{"DOI":"10.13039\/100005492","name":"Stanford University","doi-asserted-by":"publisher","award":["Stanford Graduate Fellowship"],"award-info":[{"award-number":["Stanford Graduate Fellowship"]}],"id":[{"id":"10.13039\/100005492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["F32 HL123247"],"award-info":[{"award-number":["F32 HL123247"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["U01 HG007708"],"award-info":[{"award-number":["U01 HG007708"]}],"id":[{"id":"10.13039\/100000002","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":[[2016,6,14]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Genetic variants in human \u03b2-cardiac myosin, which causes muscle contraction in the heart, can lead to hypertrophic cardiomyopathy (HCM), an inherited heart disease that can cause sudden death. New technologies have generated sequence data for large numbers of patients with HCM and unaffected individuals. In this study, we compare the protein structural locations of genetic variants of patients with HCM and the general population to identify spatial regions of the myosin that have a higher than expected proportion of genetic variants associated with HCM and earlier age at diagnosis. In addition, we develop new methods to interrogate the localization of genetic changes in protein structures. Our study demonstrates the power of combining clinical, genetic, and structural data to gain insight into Mendelian disease.<\/jats:p>","DOI":"10.1073\/pnas.1606950113","type":"journal-article","created":{"date-parts":[[2016,5,31]],"date-time":"2016-05-31T23:18:41Z","timestamp":1464736721000},"page":"6701-6706","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":126,"title":["Multidimensional structure-function relationships in human \u03b2-cardiac myosin from population-scale genetic variation"],"prefix":"10.1073","volume":"113","author":[{"given":"Julian R.","family":"Homburger","sequence":"first","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Green","sequence":"additional","affiliation":[{"name":"MyoKardia, Inc., South San Francisco, CA 94080;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen","family":"Caleshu","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret S.","family":"Sunitha","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca E.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305;"}],"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;"},{"name":"Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghu Prasad Rao","family":"Metpally","sequence":"additional","affiliation":[{"name":"Collaborative Bioinformatics Lab, Geisinger Clinic, Danville, PA 17822;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven D.","family":"Colan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Michels","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharlene M.","family":"Day","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iacopo","family":"Olivotto","sequence":"additional","affiliation":[{"name":"Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy 50134;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos D.","family":"Bustamante","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Biomedical Data Sciences, Stanford University, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick E.","family":"Dewey","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Tarrytown, NY 10591;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn Y.","family":"Ho","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Spudich","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Bangalore 560065, India;"},{"name":"Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euan A.","family":"Ashley","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2016,5,31]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00014.2005"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.4.785"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(03)00855-6"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1159\/000252808"},{"key":"e_1_3_3_5_2","first-page":"156","article-title":"Hypertrophic cardiomyopathy: Still connecting the dots between genotype and phenotype","volume":"5","author":"Jellis CL","year":"2015","unstructured":"CL Jellis, MY Desai, Hypertrophic cardiomyopathy: Still connecting the dots between genotype and phenotype. Cardiovasc Diagn Ther 5, 156\u2013159 (2015).","journal-title":"Cardiovasc Diagn Ther"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.112.963421"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.223842"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2008.04.001"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.9.3864"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-014-9542-z"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad5169"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.112.962928"},{"key":"e_1_3_3_13_2","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","author":"Lek M","year":"2015","unstructured":"M Lek, , Analysis of protein-coding genetic variation in 60,706 humans. bioRxivorg, October 30, 2015).","journal-title":"bioRxivorg"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1510926"},{"key":"e_1_3_3_15_2","first-page":"2267","article-title":"Examining Prevailing Genotype-Phenotype Correlations in Hypertrophic Cardiomyopathy Late-Breaking Clinical Trial Abstracts","volume":"132","author":"Ho CY","year":"2015","unstructured":"CY Ho, , Examining Prevailing Genotype-Phenotype Correlations in Hypertrophic Cardiomyopathy Late-Breaking Clinical Trial Abstracts. Circulation 132, 2267\u20132285 (2015).","journal-title":"Circulation"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20140324"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1080\/03610929708831995"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.04.010"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2009.05.023"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.062415899"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2014-307205"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1136\/heart.89.10.1179"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0282(199603)38:3<305::AID-BIP4>3.0.CO;2-Y"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1200113"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8974"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj1710813"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.205"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.281.7.650"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.017633"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1068"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81598-6"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2011.09.028"},{"key":"e_1_3_3_34_2","first-page":"4705","article-title":"Structure of Human beta-Cardiac Myosin Motor Domain at 3.2 A","volume":"22","author":"Winkelmann DA","year":"2011","unstructured":"DA Winkelmann, MT Miller, AM Stock, L Liu, Structure of Human beta-Cardiac Myosin Motor Domain at 3.2 A. Mol Biol Cell 22, 4705 (2011).","journal-title":"Mol Biol Cell"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2007.03.010"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1993.1626"},{"key":"e_1_3_3_37_2","unstructured":"; R Core Team The R Project for Statistical Computing. Available at www.R-project.org\/. Accessed October 31 2014. (2014)."},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-98141-3"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btg362"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3213"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10286"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.4137\/BBI.S9902"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2014.01.025"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.033886"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.02.061"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2010.08.017"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-11-0876"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22636"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000066323.15244.54"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cccn.2004.09.016"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.144"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2004.021642"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1606950113","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1606950113","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T01:02:43Z","timestamp":1649811763000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1606950113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,31]]},"references-count":52,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2016,6,14]]}},"alternative-id":["10.1073\/pnas.1606950113"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1606950113","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/039321","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,31]]},"assertion":[{"value":"2016-05-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}