title: Mitral valve disease in Marfan syndrome and related disorders.
abstract: Marfan syndrome (MFS) is a systemic disorder of the connective tissue with pleiotropic manifestations due to heterozygous FBN1 mutations and consequent upregulation of TGFβ signaling in affected tissues. Myxomatous thickening and elongation of the mitral valve (MV) leaflets commonly occur in this condition. Investigation of murine models of this disease has led to improved understanding of the mechanisms that underlie many of the phenotypic features of MFS, including MV disease. Loeys-Dietz syndrome (LDS) is a related disorder due to heterozygous mutations in the genes encoding subunits of the TGFβ receptor, and it may also involve the MV leaflets with similar elongation and thickening of the MV leaflets. Although the genetic basis and pathogenesis of nonsyndromic MV prolapse has been elusive to date, insights derived from monogenic disorders like MFS and LDS can be informative with regard to novel gene discovery and investigation into the pathogenesis of MV disease. This manuscript will review the prevalence of MV disease in MFS, its pathogenic basis as determined in mice with Fbn1 mutations, and ongoing studies that seek to better understand MV disease in the context of fibrillin-1 deficiency or excessive TGFβ signaling.
authors.affiliation: Division of Cardiology, Johns Hopkins University, Ross 1049 720 Rutland Avenue, Baltimore, MD 21205, USA. djudge@jhmi.edu
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.forename: Rosanne
authors.initials: R
authors.lastname: Rouf
authors.forename: Jennifer
authors.initials: J
authors.lastname: Habashi
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000071838:Fibrillin-1; D000071837:Fibrillins; D020022:Genetic Predisposition to Disease; D006349:Heart Valve Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D055947:Loeys-Dietz Syndrome / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D008382:Marfan Syndrome / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008943:Mitral Valve / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D044139:Receptor, Angiotensin, Type 2; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse