TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome

Institut National de la Santé et de la Recherche Médicale (INSERM) U698, Hôpital Bichat, Paris, France.
Nature Genetics (Impact Factor: 29.35). 07/2012; 44(8):916-21. DOI: 10.1038/ng.2348
Source: PubMed


A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

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Available from: Sandosh Padmanabhan, Jun 10, 2014
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    • "The online version of this article (doi:10.1007/s00439-015-1567-0) contains supplementary material, which is available to authorized users. * Danielle Majoor-Krakauer 1 3 (Boileau et al. 2012; Judge and Dietz 2005; Lindsay et al. 2012; Loeys et al. 2005; ten Dijke and Arthur 2007). The wide range of variably expressed features in these rare autosomal dominantly inherited syndromic forms of familial thoracic aneurysm includes pectus-and/or spinal deformities, joint laxity, and skin translucency and specifically for AOS, osteoarthritis and for the Loeys–Dietz syndrome, hypertelorism, bifid uvula or cleft palate and arterial tortuosity. "
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    ABSTRACT: Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon-intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty-three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA.
    Human Genetics 05/2015; 134(8). DOI:10.1007/s00439-015-1567-0 · 4.82 Impact Factor
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    • ". This concept was replaced by findings that mutations are activating [50]. Recent genetic findings demonstrate that loss-of-function mutations in the ligand, TGFβ2, cause aortic disease [54] [55]. Thus, " paradoxical " [55] mechanisms involving both loss-offunction mutations and activation of TGFβ signaling are now proposed to underlie aortic disease. "
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    ABSTRACT: The fibrillins, large extracellular matrix molecules, polymerize to form "microfibrils." The fibrillin microfibril scaffold is populated by microfibril-associated proteins and by growth factors, which are likely to be latent. The scaffold, associated proteins, and bound growth factors, together with cellular receptors that can sense the microfibril matrix, constitute the fibrillin microenvironment. Activation of TGFβ signaling is associated with the Marfan syndrome, which is caused by mutations in fibrillin-1. Today we know that mutations in fibrillin-1 cause the Marfan syndrome as well as Weill-Marchesani syndrome (and other acromelic dysplasias) and result in opposite clinical phenotypes: tall or short stature; arachnodactyly or brachydactyly; joint hypermobility or stiff joints; hypomuscularity or hypermuscularity. We also know that these different syndromes are associated with different structural abnormalities in the fibrillin microfibril scaffold and perhaps with specific cellular receptors (mechanosensors). How does the microenvironment, framed by the microfibril scaffold and populated by latent growth factors, work? We must await future investigations for the molecular and cellular mechanisms that will answer this question. However, today we can appreciate the importance of the fibrillin microfibril niche as a contextual environment for growth factor signaling and potentially for mechanosensation. Copyright © 2015. Published by Elsevier B.V.
    Matrix biology: journal of the International Society for Matrix Biology 05/2015; 142. DOI:10.1016/j.matbio.2015.05.002 · 5.07 Impact Factor
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    • "Moreover, how these signaling axes regulate gene expression programs and contribute to reduced ECM proteins as seen in our proteomic study of KC [22] are not well understood. Interestingly, a group of heritable connective tissue diseases which include syndromic aortic aneurisms, including Marfan syndrome, Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, all associated with vessel wall weakening, have been traced back to genetic variants in multiple components of the TGFβ signal network [62], [63]. Keratoconus may share certain molecular pathways with these diseases, opening new avenues to research its pathogenesis. "
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    ABSTRACT: Keratoconus (KC) is a complex thinning disease of the cornea that often requires transplantation. The underlying pathogenic molecular changes in this disease are poorly understood. Earlier studies reported oxidative stress, metabolic dysfunctions and accelerated death of stromal keratocytes in keratoconus (KC) patients. Utilizing mass spectrometry we found reduced stromal extracellular matrix (ECM) proteins in KC, suggesting ECM-regulatory changes that may be due to altered TGFβ signals. Here we investigated properties of stromal cells from donor (DN) and KC corneas grown as fibroblasts in serum containing DMEM: F12 or in serum-free medium containing insulin, transferrin, selenium (ITS). Phosphorylation of SMAD2/3 of the canonical TGFβ pathway, was high in serum-starved DN and KC fibroblast protein extracts, but pSMAD1/5/8 low at base line, was induced within 30 minutes of TGFβ1 stimulation, more so in KC than DN, suggesting a novel TGFβ1-SMAD1/5/8 axis in the cornea, that may be altered in KC. The serine/threonine kinases AKT, known to regulate proliferation, survival and biosynthetic activities of cells, were poorly activated in KC fibroblasts in high glucose media. Concordantly, alcohol dehydrogenase 1 (ADH1), an indicator of increased glucose uptake and metabolism, was reduced in KC compared to DN fibroblasts. By contrast, in low glucose (5.5 mM, normoglycemic) serum-free DMEM and ITS, cell survival and pAKT levels were comparable in KC and DN cells. Therefore, high glucose combined with serum-deprivation presents some cellular stress difficult to overcome by the KC stromal cells. Our study provides molecular insights into AKT and TGFβ signal changes in KC, and a mechanism for functional studies of stromal cells from KC corneas.
    PLoS ONE 09/2014; 9(9):e106556. DOI:10.1371/journal.pone.0106556 · 3.23 Impact Factor
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