DZIP1 regulates mammalian cardiac valve development through a Cby1-β-catenin mechanism

Mitral valve prolapse (MVP) is a common and progressive cardiovascular disease with developmental origins. How developmental errors contribute to disease pathogenesis are not well understood.

A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and β-catenin. Co-expression 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 β-catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of β-catenin with effects on transcriptional activity. A mutation within this domain was identified in a family with inherited non-syndromic MVP. This novel mutation and our previously identified DZIP1^S24R variant resulted in reduced DZIP1 and CBY1 stability and increased β-catenin activities. The β-catenin target gene, MMP2 was up-regulated in the Dzip1^S14R/+ valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype.

Dzip1 functions to restrain β-catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear β-catenin/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype.