New recessive truncating mutation in <i>LTBP3</i> in a family with oligodontia, short stature, and mitral valve prolapse

Dugan, Sarah; Temme, Renee; Olson, Rebecca; Mikhailov, Anna; Law, Rosalind; Mahmood, Huda; Noor, Abdul; Vincent, John B.

doi:10.1002/ajmg.a.37049

Cited by 23 publications

(21 citation statements)

References 13 publications

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“…Previous studies have established a link between increased growth factor signaling and syndromic forms of myxomatous mitral valve disease. For instance, patients with Marfan syndrome, a connective tissue disease that can result in myxomatous mitral valves and MVP, have indicated increased Erk1/2 signaling as a potential pathogenic mediator of the disease [ 17 , 18 , 19 , 20 , 21 ]. Marfan syndrome is caused by mutations in FBN1 ( Fibrillin-1 ), which result in excessive TGFβsignaling due to diminished binding of the latent form of the growth factor.…”

Section: Resultsmentioning

confidence: 99%

Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease

Sauls

Toomer

Williams

et al. 2015

JCDD

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Mutations in the actin-binding gene Filamin-A have been linked to non-syndromic myxomatous valvular dystrophy and associated mitral valve prolapse. Previous studies by our group traced the adult valve defects back to developmental errors in valve interstitial cell-mediated extracellular matrix remodeling during fetal valve gestation. Mice deficient in Filamin-A exhibit enlarged mitral leaflets at E17.5, and subsequent progression to a myxomatous phenotype is observed by two months. For this study, we sought to define mechanisms that contribute to myxomatous degeneration in the adult Filamin-A-deficient mouse. In vivo experiments demonstrate increased infiltration of hematopoietic-derived cells and macrophages in adolescent Filamin-A conditional knockout mice. Concurrent with this infiltration of hematopoietic cells, we show an increase in Erk activity, which localizes to regions of MMP2 expression. Additionally, increases in cell proliferation are observed at two months, when hematopoietic cell engraftment and signaling are pronounced. Similar changes are observed in human myxomatous mitral valve tissue, suggesting that infiltration of hematopoietic-derived cells and/or increased Erk signaling may contribute to myxomatous valvular dystrophy. Consequently, immune cell targeting and/or suppression of pErk activities may represent an effective therapeutic option for mitral valve prolapse patients.

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Section: Resultsmentioning

confidence: 99%

Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease

Sauls

Toomer

Williams

et al. 2015

JCDD

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“…All heterozygous parents were reported as healthy with normal dentition. Most recently, two siblings with oligodontia, short stature and mitral valve prolapse were found to be homozygous for a single base insertion (c.1858_1859insG) leading to a frameshift and premature truncation after 171 amino acids (p.Cys620Trpfs*171) 30. The functional consequences of each mutation in differing protein domains may explain the wide clinical variability observed within the LTPB3 variant spectrum.…”

Section: Discussionmentioning

confidence: 99%

Mutations inLTBP3cause acromicric dysplasia and geleophysic dysplasia

et al. 2016

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“…Mutations in human LTBP3 were first observed in a consanguineous Pakistani family, in which all affected members presented with short stature, vertebral and skull bone alterations, and oligodontia . In another family, two sisters with homozygous‐recessive truncating mutations in LTBP3 also had oligodontia, short stature, and mitral valve prolapse . Our published report identified recessive hypomorphic LTBP3 mutations (including deletion, nonsense, and aberrant splice mutations) in patients with dental anomalies and short stature (MIM; 601216) or Verloes Bourguignon syndrome .…”

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confidence: 81%

Enamel and dental anomalies in latent‐transforming growth factor beta‐binding protein 3 mutant mice

Morkmued

Hemmerlé

Mathieu

et al. 2017

European J Oral Sciences

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Latent‐transforming growth factor beta‐binding protein 3 (LTBP‐3) is important for craniofacial morphogenesis and hard tissue mineralization, as it is essential for activation of transforming growth factor‐β (TGF‐β). To investigate the role of LTBP‐3 in tooth formation we performed micro‐computed tomography (micro‐CT), histology, and scanning electron microscopy analyses of adult Ltbp3‐/‐ mice. The Ltbp3‐/‐ mutants presented with unique craniofacial malformations and reductions in enamel formation that began at the matrix formation stage. Organization of maturation‐stage ameloblasts was severely disrupted. The lateral side of the incisor was affected most. Reduced enamel mineralization, modification of the enamel prism pattern, and enamel nodules were observed throughout the incisors, as revealed by scanning electron microscopy. Molar roots had internal irregular bulbous‐like formations. The cementum thickness was reduced, and microscopic dentinal tubules showed minor nanostructural changes. Thus, LTBP‐3 is required for ameloblast differentiation and for the formation of decussating enamel prisms, to prevent enamel nodule formation, and for proper root morphogenesis. Also, and consistent with the role of TGF‐β signaling during mineralization, almost all craniofacial bone components were affected in Ltbp3‐/‐ mice, especially those involving the upper jaw and snout. This mouse model demonstrates phenotypic overlap with Verloes Bourguignon syndrome, also caused by mutation of LTBP3, which is hallmarked by craniofacial anomalies and amelogenesis imperfecta phenotypes.

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New recessive truncating mutation in LTBP3 in a family with oligodontia, short stature, and mitral valve prolapse

Cited by 23 publications

References 13 publications

Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease

Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease

Mutations inLTBP3cause acromicric dysplasia and geleophysic dysplasia

Enamel and dental anomalies in latent‐transforming growth factor beta‐binding protein 3 mutant mice

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