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.