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How developmental errors contribute to disease pathogenesis are not well understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and \u03b2\u2010catenin. Co\u2010expression during valve development revealed overlap at the basal body of the primary cilia. Biochemical studies revealed a DZIP1 peptide required for stabilization of the complex and suppression of \u03b2\u2010catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of \u03b2\u2010catenin with effects on transcriptional activity. A mutation within this domain was identified in a family with inherited non\u2010syndromic MVP. This novel mutation and our previously identified <jats:italic>DZIP1<\/jats:italic><jats:sup><jats:italic>S24R<\/jats:italic><\/jats:sup> variant resulted in reduced DZIP1 and CBY1 stability and increased \u03b2\u2010catenin activities. The \u03b2\u2010catenin target gene, MMP2 was up\u2010regulated in the <jats:italic>Dzip1<\/jats:italic><jats:sup><jats:italic>S14R\/+<\/jats:italic><\/jats:sup> valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Dzip1 functions to restrain \u03b2\u2010catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear \u03b2\u2010catenin\/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dvdy.342","type":"journal-article","created":{"date-parts":[[2021,4,2]],"date-time":"2021-04-02T22:38:48Z","timestamp":1617403128000},"page":"1432-1449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<scp>DZIP1<\/scp> regulates mammalian cardiac valve development through a Cby1\u2010\u03b2\u2010catenin mechanism"],"prefix":"10.1002","volume":"250","author":[{"given":"Lilong","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology Medical University of South Carolina  Charleston South Carolina 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