Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Helen B Taussig Children's Heart Center, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nature Genetics (Impact Factor: 29.35). 07/2012; 44(8):922-7. DOI: 10.1038/ng.2349
Source: PubMed


Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.

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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 d.majoor-krakauer@erasmusmc.nl 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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    • "Since degradation of the vascular wall in aortic aneurysms is related to disturbances in the TGF-β signaling pathway [14], [21], we next investigated the role of TGF-β signaling in alveolar wall degradation in Fibulin-4 deficient mice. Although the gene expression analysis in lung mRNA samples only gave rise to a limited set of deregulated genes in newborn Fibulin-4R/R animals, it did reveal downregulation of the Pias4 gene in Fibulin-4R/R compared to Fibulin-4+/+ lungs (1.2-fold, p<0.05, "
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    ABSTRACT: Background In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease. Methods We first determined the prevalence of chronic obstructive pulmonary disease in a clinical cohort of aortic aneurysms patients and arterial occlusive disease patients. Subsequently, we used a combined approach comprising pathological, functional, molecular imaging, immunological and gene expression analysis to reveal the sequence of events that culminates in pulmonary emphysema in aneurysmal Fibulin-4 deficient (Fibulin-4R) mice. Results Here we show that COPD is significantly more prevalent in aneurysm patients compared to arterial occlusive disease patients, independent of smoking, other clinical risk factors and inflammation. In addition, we demonstrate that aneurysmal Fibulin-4R/R mice display severe developmental lung emphysema, whereas Fibulin-4+/R mice acquire alveolar breakdown with age and upon infectious stress. This vicious circle is further exacerbated by the diminished antiprotease capacity of the lungs and ultimately results in the development of pulmonary emphysema. Conclusions Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation.
    PLoS ONE 09/2014; 9(9):e106054. DOI:10.1371/journal.pone.0106054 · 3.23 Impact Factor
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    • "The TGFB2 gene is also involved with Loyes-Dietz syndrome 4 (OMIM #614816) caused by heterozygous mutation in the TGFB2 gene. Lindsay et al. [18] identified two unrelated patients with aortic aneurysm and de novo 1q41 microdeletions encompassing the TGFB2, one with Marfan syndrome and the other with Loyes-Dietz syndrome-like features. The RYR2 gene, which maps to 1q42q43, encodes a ryanodine receptor found in cardiac muscle. "
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    ABSTRACT: Background Partial duplication 1q is a rare cytogenetic anomaly frequently associated to deletion of another chromosome, making it difficult to define the precise contribution of the different specific chromosomal segments to the clinical phenotype. Case presentation We report a clinical and cytogenomic study of a patient with multiple congenital anomalies, heart defect, neuromotordevelopment delay, intellectual disability, who presents partial trisomy 1q32 and partial monosomy 11q25 inherited from a paternal balanced translocation identified by chromosome microarray and fluorescence in situ hybridization. Conclusion Compared to patients from the literature, the patient’s phenotype is more compatible to the 1q32 duplication’s clinical phenotype, although some clinical features may also be associated to the deleted segment on chromosome 11. This is the smallest 11q terminal deletion ever reported and the first association between 1q32.3 duplication and 11q25 deletion in the literature.
    Molecular Cytogenetics 08/2014; 7(1):57. DOI:10.1186/s13039-014-0057-8 · 2.14 Impact Factor
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