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Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor <jats:italic>NKX2-5<\/jats:italic> cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between <jats:italic>Nkx2<\/jats:italic>-<jats:italic>5<\/jats:italic> and <jats:italic>Sarcospan (Sspn<\/jats:italic>) that affects the risk of muscular VSD in mice. <jats:italic>Sspn<\/jats:italic> encodes a protein in the dystrophin-glycoprotein complex. <jats:italic>Sspn<\/jats:italic> knockout (<jats:italic>Sspn<\/jats:italic><jats:sup>KO<\/jats:sup>) mice do not have heart defects, but <jats:italic>Nkx2-5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>\/<jats:italic>Sspn<\/jats:italic><jats:sup>KO<\/jats:sup> mutants have a higher incidence of muscular VSD than <jats:italic>Nkx2<\/jats:italic>-<jats:italic>5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the <jats:italic>Nkx2-5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>\/<jats:italic>Sspn<\/jats:italic><jats:sup>KO<\/jats:sup> mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, <jats:italic>Nkx2-5<\/jats:italic> and <jats:italic>Sspn<\/jats:italic> act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs.<\/jats:p>","DOI":"10.1038\/srep46438","type":"journal-article","created":{"date-parts":[[2017,4,13]],"date-time":"2017-04-13T09:47:01Z","timestamp":1492076821000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart"],"prefix":"10.1038","volume":"7","author":[{"given":"Adam A.","family":"Panzer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk D.","family":"Regmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DePorres","family":"Cormier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan T.","family":"Danzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iuan-bor D.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia B.","family":"Winston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alayna K.","family":"Hutchinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Salm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire E.","family":"Schulkey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca S.","family":"Cochran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick Y.","family":"Jay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,13]]},"reference":[{"key":"BFsrep46438_CR1","unstructured":"E. 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