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Here we describe a novel <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content> mutation in the myosin regulatory light chain (<jats:styled-content style=\"fixed-case\">RLC<\/jats:styled-content>), in which aspartic acid at position 94 is replaced by alanine (D94A). The mutation was identified by exome sequencing of three adult first\u2010degree relatives who met formal criteria for idiopathic <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>. To obtain insight into the functional significance of this pathogenic <jats:italic><jats:styled-content style=\"fixed-case\">MYL<\/jats:styled-content>2<\/jats:italic> variant, we cloned and purified the human ventricular <jats:styled-content style=\"fixed-case\">RLC<\/jats:styled-content> wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) and D94A mutant proteins, and performed <jats:italic>in\u00a0vitro<\/jats:italic> experiments using <jats:styled-content style=\"fixed-case\">RLC<\/jats:styled-content>\u2010mutant or WT\u2010reconstituted porcine cardiac preparations. The mutation induced a reduction in the \u03b1\u2010helical content of the <jats:styled-content style=\"fixed-case\">RLC<\/jats:styled-content>, and imposed intra\u2010molecular rearrangements. The phosphorylation of <jats:styled-content style=\"fixed-case\">RLC<\/jats:styled-content> by Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010activated myosin light chain kinase was not affected by D94A. The mutation was seen to impair binding of <jats:styled-content style=\"fixed-case\">RLC<\/jats:styled-content> to the myosin heavy chain, and its incorporation into <jats:styled-content style=\"fixed-case\">RLC<\/jats:styled-content>\u2010depleted porcine myosin. The actin\u2010activated <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase activity of mutant\u2010reconstituted porcine cardiac myosin was significantly higher compared with <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase of wild\u2010type. No changes in the myofibrillar <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase\u2013<jats:styled-content style=\"fixed-case\">pC<\/jats:styled-content>a relationship were observed in wild\u2010type\u2010 or D94A\u2010reconstituted preparations. Measurements of contractile force showed a slightly reduced maximal tension per cross\u2010section of muscle, with no change in the calcium sensitivity of force in D94A\u2010reconstituted skinned porcine papillary muscle strips compared with wild\u2010type. Our data indicate that subtle structural rearrangements in the <jats:styled-content style=\"fixed-case\">RLC<\/jats:styled-content> molecule, followed by its impaired interaction with the myosin heavy chain, may trigger functional abnormalities contributing to the <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content> phenotype.<\/jats:p>","DOI":"10.1111\/febs.13286","type":"journal-article","created":{"date-parts":[[2015,3,31]],"date-time":"2015-03-31T03:11:10Z","timestamp":1427771470000},"page":"2379-2393","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Novel familial dilated cardiomyopathy mutation in <i><scp>MYL<\/scp>2<\/i> affects the structure and function of myosin regulatory light chain"],"prefix":"10.1111","volume":"282","author":[{"given":"Wenrui","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Pharmacology University of Miami Miller School 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School of Medicine Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Morales","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Department of Internal Medicine Wexner Medical Center Ohio State University Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim L.","family":"McBride","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Ohio State University Center for Cardiovascular and Pulmonary Research Nationwide Children's Hospital Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Fitzgerald\u2010Butt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Ohio State University Center for Cardiovascular and Pulmonary Research Nationwide Children's Hospital Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ray 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