Discussion
We report a family with MVP and a missense variant in PDLIM7 co-segregating with the phenotype and predicted to be likely pathogenic by several functional annotation algorithms and we therefore suggestPDLMI7 as a possible novel candidate gene for familial MVP.
The function of Pdlim7 was previously investigated in zebrafish and mice. In zebrafish, Pdlim7 transcripts were detected in the developing heart. These zebrafish models also revealed that Pdlim7 is able to regulate the subcellular localization and transcriptional activity of Tbx5(13). Tbx5 binds to Pdlim7 along cytoplasmic actin filaments after leaving the nucleus. The sequestration of Tbx5 by Pdlim7 prevents the transcription factor from activating target genes in the nucleus. TBX5 is a gene known to be involved in cardiovascular development in humans and mutations in TBX5 result in cardiac malformations as seen in the Holt-Oram syndrome(16). Specifically, the Holt-Oram syndrome is caused by missense mutations in the TBX5 gene resulting mostly in a loss of function of the tbx5 protein, leading to upper limb and cardiac malformations, including mitral valve abnormalities such as MVP (17-19). Knock-down of Pdlim7 in zebrafish resulted in developmental heart malformations due to failure of looping of the developing heart. Loss of Pdlim7 function in the heart tube could lead to Tbx5-independent misregulation of the actin cytoskeleton, resulting in these heart shape malformations. More specifically, knock-down of Pdlim7 in zebrafish embryos resulted in the absence of valve tissue despite the differentiation of myocardial and endocardial cell layers. On the contrary, lack of Tbx5 function while Pdlim7 function was intact, led to increased valve leaflet tissue compared to wild-type zebrafish hearts(14). Theoretically, a mutation in Pdlim7 resulting in inhibition of Tbx5 could therefore lead to valve abnormalities.
In mice, Pdlim7 transcripts were detected in the atria, trabeculated regions of the ventricles and the septa. Moreover, the Pdlim7 protein was found in the developing atrioventricular and outflow tract cushions of the heart. Pdlim7 knock-out mice showed normal early cardiac valve development. However, echocardiography on 3-months old Pdlim7 knock-out mice showed increased mitral and tricuspid valve annulus diameter compared to wild-type mice. Histological analysis of the mitral and tricuspid valves of the Pdlim7 knock-out mice showed an elongation of the leaflets of the valves, suggesting an abnormal remodelling of the mitral and tricuspid valve in the absence of Pdlim7 at a later stage of development(15). A possible explanation could be that Pdlim7 has a yet unknown function in epicardial-derived cells that supports valve remodelling(20).
These results of Pdlim7 in zebrafish and mice, in addition to evidence coming from TBX5 studies, indicate that there could also be a role for Pdlim7 in valvular abnormalities in humans. Our family with familial MVP and a co-segregating missense variant in the PDLIM7 gene is a first indication of such a possibility, even though further research and functional studies will be necessary to confirm the causal relationship.