Syndromic and non‐syndromic aneurysms of the human ascending aorta share activation of the Smad2 pathway

Gomez, Delphine; Zen, Ayman Al Haj; Borges, Lívia de Oliveira; Philippe, Monique; Gutierrez, Paulo Sampaio; Jondeau, Guillaume; Michel, Jean‐Baptiste; Vranckx, Roger

doi:10.1002/path.2516

Cited by 165 publications

(140 citation statements)

References 52 publications

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“…26 Conversely, ACTA2/MYH11 mutations affect the contractile apparatus of the vascular smooth muscle cells rather than TGF-β1 signaling. Therefore, lower TGF-β1 levels may be expected from the underlying major pathomechanism despite some evidence for upregulation of TGF-β1 signaling in ACTA2 and MYH11 mutations with TAAD.…”

Section: Discussionmentioning

confidence: 99%

Total Serum Transforming Growth Factor‐β1 Is Elevated in the Entire Spectrum of Genetic Aortic Syndromes

Hillebrand

Millot

Sheikhzadeh

et al. 2014

Clinical Cardiology

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Background: Total serum transforming growth factor-beta 1 (tsTGF-β1) is increased in patients with Marfan syndrome (MFS), but it has not been assessed in thoracic aortic aneurysm and dissection (TAAD), Loeys-Dietz syndrome (LDS), and bicuspid aortic valve disease (BAVD). Hypothesis: tsTGF-β1 is increased in genetic aortic syndromes including TAAD, LDS, MFS, and BAVD. Methods: We measured tsTGF-β1 and performed sequencing of the genes FBN1, TGFBR1, and TGFBR2 in 317 consecutive patients with suspected or known genetic aortic syndrome (167 men, 150 women; mean age 43 ± 14 years). TAAD was diagnosed in 20, LDS in 20, MFS in 128, and BAVD in 30 patients, and genetic aortic syndrome was excluded in 119 patients. Results: Elevated tsTGF-β1 levels were associated with causative gene mutations (P = 0.008), genetic aortic syndrome (P = 0.009), and sporadic occurrence of genetic aortic syndrome (P = 0.048), whereas only genetic aortic syndrome qualified as an independent predictor of tsTGF-β1 (P = 0.001). The tsTGF-β1 levels were elevated in FBN1 and NOTCH1 mutations vs patients without mutations (both P = 0.004), and in NOTCH1 mutations vs ACTA2/MYH11 mutations (P = 0.015). Similarly, tsTGF-β1 levels were elevated in MFS (P = 0.003) and in BAVD (P = 0.006) vs patients without genetic aortic syndrome. In contrast to specific clinical features of MFS, FBN1 in-frame mutations (P = 0.019) were associated with increased tsTGF-β1 levels. Conclusions: tsTGF-β1 is elevated in the entire spectrum of genetic aortic syndromes. However, gradual differences in the increases of tsTGF-β1 levels may mirror different degrees of alteration of tsTGF-β1 signaling in different genetic aortic syndromes.

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Section: Discussionmentioning

confidence: 99%

Total Serum Transforming Growth Factor‐β1 Is Elevated in the Entire Spectrum of Genetic Aortic Syndromes

Hillebrand

Millot

Sheikhzadeh

et al. 2014

Clinical Cardiology

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“…1, 8 Indeed, several lines of evidence indicate augmented TGF-b signalling in aortic lesions in vivo. 6,9,10 This is intriguing as many pathogenic mutations associated with TAAD have a loss-of-function effect. 2,11,12 Recently, two studies have shown that haploinsufficiency for TGFB2 causes a familial syndrome of TAAD with additional clinical manifestations overlapping MFS and LDS.…”

Section: Introductionmentioning

confidence: 99%

A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm

et al. 2013

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A number of autosomal dominantly inherited disorders, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), are associated with predisposition to thoracic aortic aneurysms and dissections (TAADs). In the majority of cases, mutations in genes encoding components of the transforming growth factor-b (TGF-b) signaling pathway, such as FBN1, TGFBR1, TGFBR2 and SMAD3, underlie the disease. Recently, a familial syndromic form of TAAD with other clinical features that overlap the MFS-LDS spectrum has been described to be caused by heterozygous loss-of-function mutations in TGFB2, encoding the TGF-b2 ligand of TGF-b serine/threonine kinase receptors (TGFBRs). We analyzed the TGFB2 gene by sequencing in a cohort of 88 individuals with a Marfan-like phenotype and/or TAAD, who did not have mutations in known genes causing thoracic aortic disease. We identified the novel heterozygous c.1165dupA mutation in exon 7 of TGFB2 in three members of a family, a 51-year-old male, his brother and nephew with aortic aneurysms, cervical arterial tortuosity and/or skeletal abnormalities as well as craniofacial dysmorphisms. The 1-bp duplication causes a frameshift leading to a stable transcript with a premature stop codon after seven TGF-b2-unrelated amino acids (p.Ser389Lysfs*8). As the resulting protein is unlikely functional and by considering data from the literature, we support the notion that functional haploinsufficiency for TGF-b2 predisposes to thoracic aortic disease. Taken together, TGFB2 is a rarely mutated gene in patients with syndromic TAAD, and the clinical features of our TGFB2 mutation-positive individuals fit in the scheme of LDS, rather than MFS-related disorders.

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“…Dysregulation of the TGF-β signaling pathways is seen in other aneurysmal diseases including Marfan syndrome, owing to a mutation of the FBN1 gene, and Loeys-Dietz syndrome, through a mutation of the TGFB2 gene 4 .…”

Section: To the Editormentioning

confidence: 99%

A Case of Rheumatoid Arthritis Associated withSMAD3Gene Mutation: A New Clinical Entity?

et al. 2015

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Syndromic and non‐syndromic aneurysms of the human ascending aorta share activation of the Smad2 pathway

Cited by 165 publications

References 52 publications

Total Serum Transforming Growth Factor‐β1 Is Elevated in the Entire Spectrum of Genetic Aortic Syndromes

Total Serum Transforming Growth Factor‐β1 Is Elevated in the Entire Spectrum of Genetic Aortic Syndromes

A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm

A Case of Rheumatoid Arthritis Associated withSMAD3Gene Mutation: A New Clinical Entity?

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