{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T10:50:15Z","timestamp":1791975015133,"version":"4.4.0"},"reference-count":62,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,12,26]],"date-time":"2013-12-26T00:00:00Z","timestamp":1388016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"OPTISTEM through the European Union 7th Framework Programme supported JS","award":["223098"],"award-info":[{"award-number":["223098"]}]},{"name":"Medical Research Council","award":["(G1100193)"],"award-info":[{"award-number":["(G1100193)"]}]},{"name":"The Medical Research Council under which this work was initiated","award":["G0700307"],"award-info":[{"award-number":["G0700307"]}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["NH\/12\/2\/29427. The Zammit lab also acknowledges financial support from the Muscular Dystrophy Campaign, Association Francaise contre les Myopathies and BIODESIGN (contract 262948-2) through the European Union 7th Framework Programme"],"award-info":[{"award-number":["NH\/12\/2\/29427. The Zammit lab also acknowledges financial support from the Muscular Dystrophy Campaign, Association Francaise contre les Myopathies and BIODESIGN (contract 262948-2) through the European Union 7th Framework Programme"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Mutations in A\u2010type nuclear lamins cause laminopathies. However, genotype\u2013phenotype correlations using the 340 missense mutations within the\n                    <jats:italic>LMNA<\/jats:italic>\n                    gene are unclear: partially due to the limited availability of three\u2010dimensional structure. The immunoglobulin (Ig)\u2010like fold domain has been solved, and using bioinformatics tools (including Polyphen\u20102, Fold X, Parameter OPtimized Surfaces, and PocketPicker) we characterized 56 missense mutations for position, surface exposure, change in charge and effect on Ig\u2010like fold stability. We find that 21 of the 27 mutations associated with a skeletal muscle phenotype are distributed throughout the Ig\u2010like fold, are nonsurface exposed and predicted to disrupt overall stability of the Ig\u2010like fold domain. Intriguingly, the remaining 6 mutations clustered, had higher surface exposure, and did not affect stability. The majority of 9 lipodystrophy or 10 premature aging syndrome mutations also did not disrupt Ig\u2010like fold domain stability and were surface exposed and clustered in distinct regions that overlap predicted binding pockets. Although buried, the 10 cardiac mutations had no other consistent properties. Finally, most lipodystrophy and premature aging mutations resulted in a \u20101 net charge change, whereas skeletal muscle mutations caused no consistent net charge changes. Since premature aging, lipodystrophy and the subset of 6 skeletal muscle mutations cluster tightly in distinct, charged regions, they likely affect lamin A\/C \u2013protein\/DNA\/RNA interactions: providing a consistent genotype\u2013phenotype relationship for mutations in this domain. Thus, this subgroup of skeletal muscle laminopathies that we term the \u2018Skeletal muscle cluster\u2019, may have a distinct pathological mechanism. These novel associations refine the ability to predict clinical features caused by certain\n                    <jats:italic>LMNA<\/jats:italic>\n                    missense mutations. Proteins 2014; 82:904\u2013915. \u00a9 2013 Wiley Periodicals, Inc.\n                  <\/jats:p>","DOI":"10.1002\/prot.24465","type":"journal-article","created":{"date-parts":[[2013,11,9]],"date-time":"2013-11-09T03:12:48Z","timestamp":1383966768000},"page":"904-915","source":"Crossref","is-referenced-by-count":33,"title":["Mapping disease\u2010related missense mutations in the immunoglobulin\u2010like fold domain of lamin A\/C reveals novel genotype\u2013phenotype associations for laminopathies"],"prefix":"10.1002","volume":"82","author":[{"given":"Juergen","family":"Scharner","sequence":"first","affiliation":[{"name":"Randall Division of Cell and Molecular Biophysics King's College London London SE1 1UL United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui\u2010Chun","family":"Lu","sequence":"additional","affiliation":[{"name":"Randall Division of Cell and Molecular Biophysics King's College London London SE1 1UL United 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