Developmental basis for filamin-A-associated myxomatous mitral valve disease

Kimberly Sauls, Annemarieke De Vlaming, Brett S. Harris, Katherine Williams, Andy Wessels, Robert A. Levine, Susan A. Slaugenhaupt, Richard L. Goodwin, Luigi Michele Pavone, Jean Merot, Jean Jacques Schott, Thierry Le Tourneau, Thomas Dix, Sean Jesinkey, Yuanyi Feng, Christopher Walsh, Bin Zhou, Scott Baldwin, Roger R. Markwald, Russell A. Norris

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


AimsWe hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development.Methods and resultsFilamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype.ConclusionsThese findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.

Original languageEnglish (US)
Pages (from-to)109-119
Number of pages11
JournalCardiovascular research
Issue number1
StatePublished - Oct 1 2012


  • Filamin-A
  • Myxomatous valve disease
  • Serotonin
  • Transglutaminase-2
  • Valve maturation

ASJC Scopus subject areas

  • General Medicine


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