Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD

Renard, Marjolijn; Callewaert, Bert; Baetens, Machteld; Campens, Laurence; MacDermot, K D; Fryns, J. P.; Bonduelle, M; Dietz, Harry C.; Gaspar, Isabel; Cavaco, Diogo; Stattin, Eva; Schrander-Stumpel, C. T. R. M.; Coucke, Paul; Loeys, Bart; Paepe, Anne De; Backer, Julie De

doi:10.1016/j.ijcard.2011.08.079

Cited by 142 publications

(112 citation statements)

References 33 publications

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“…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. 27 Finally, our finding of increased tsTGF-β1 in LDS is novel and supports LDS as a disease with upregulation of TGF-β1 signaling. e Measurements were obtained on magnetic resonance imaging at the time of tsTGF-β1 measurements.…”

Section: Discussionsupporting

confidence: 61%

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: Discussionsupporting

confidence: 61%

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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“…Our results also suggest that genetic testing and cardiac imaging with at least TTE should be offered to all FDRs and SDRs of patients with suspected NS‐TADs. Mutation carriers should undergo further imaging (MRI or CT scan), focusing on thoracic aorta and/or other arterial trees based on the causative gene mutation 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74. For example, ACTA2‐mutation carriers should be monitored for coronary artery disease and occlusive cerebrovascular disease, in addition to the currently recommended routine imaging tests 32.…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

Mariscalco

Debiec

Elefteriades

et al. 2018

JAHA

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BackgroundNonsyndromic thoracic aortic diseases (NS‐TADs) are often silent entities until they present as life‐threatening emergencies. Despite familial inheritance being common, screening is not the current standard of care in NS‐TADs. We sought to determine the incidence of aortic diseases, the predictive accuracy of available screening tests, and the effectiveness of screening programs in relatives of patients affected by NS‐TADs.Methods and ResultsA systematic literature search on PubMed/MEDLINE, Embase, and the Cochrane Library was conducted from inception to the end of December 2017. The search was supplemented with the Online Mendelian Inheritance in Man database. A total of 53 studies were included, and a total of 2696 NS‐TAD relatives were screened. Screening was genetic in 49% of studies, followed by imaging techniques in 11% and a combination of the 2 in 40%. Newly affected individuals were identified in 33%, 24%, and 15% of first‐, second‐, and third‐degree relatives, respectively. Familial NS‐TADs were primarily attributed to single‐gene mutations, expressed in an autosomal dominant pattern with incomplete penetrance. Specific gene mutations were observed in 25% of the screened families. Disease subtype and genetic mutations stratified patients with respect to age of presentation, aneurysmal location, and aortic diameter before dissection. Relatives of patients with sporadic NS‐TADs were also found to be affected. No studies evaluated the predictive accuracy of imaging or genetic screening tests, or the clinical or cost‐effectiveness of an NS‐TAD screening program.ConclusionsFirst‐ and second‐degree relatives of patients affected by both familial and sporadic NS‐TADs may benefit from personalized screening programs.

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“…9 Immunohistochemistry staining of aortic biopsy specimens from a patient and family member with an MYH11 also demonstrated upregulation of the transforming growth factor-b (TGF-b) signaling pathway. 27 At the molecular level, patients with TAAD harbor the mutation identified in our patient, which leads to the amino acid alteration of p.Arg1758Gln, together with the IVS32+1G > T allelic variant. Together this mutation and variant results in an in-frame deletion and the loss of exon 32 encoding 71 amino acids.…”

Section: Myosin Heavy Chain 11mentioning

confidence: 72%

“…27 Mutations in MYH11 have been identified in 2 families with autosomal dominant inheritance leading to TAAD in conjunction with patent ductus arteriosus. 40 The hypothesized mechanism is a disturbance in contractile smooth muscle cell function leading to lower aortic compliance and elastolysis with focal vascular smooth muscle hyperplasia.…”

Section: Myosin Heavy Chain 11mentioning

confidence: 99%

Rapid de novo aneurysm formation after clipping of a ruptured middle cerebral artery aneurysm in an infant with an MYH11 mutation

Ravindra

Karsy

Schmidt

et al. 2016

PED

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The authors report the case of a previously healthy 6-month-old girl who presented with right arm and leg stiffening consistent with seizure activity. An initial CT scan of the head demonstrated acute subarachnoid hemorrhage in the basal cisterns extending into the left sylvian fissure. Computed tomography angiography demonstrated a 7 × 6 × 5–mm saccular aneurysm of the inferior M2 division of the left middle cerebral artery. The patient underwent left craniotomy and microsurgical clip ligation with wrapping of the aneurysm neck because the vessel appeared circumferentially dysplastic in the region of the aneurysm. Postoperative angiography demonstrated a small remnant, sluggish distal flow, but no significant cerebral vasospasm. Fifty-five days after the initial aneurysm rupture, the patient presented again with an acute intraparenchymal hemorrhage of the left anterior temporal lobe. Angiogram revealed a circumferentially dysplastic superior division of the M2 branch, with a new 5 × 4–mm saccular aneurysm distinct from the first, with 2 smaller aneurysms distal to the new ruptured aneurysm. Endovascular parent vessel occlusion with Onyx was performed. Genetic testing revealed a mutation of the MYH11. To the authors' knowledge, this is the first report of rapid de novo aneurysm formation in an infant with an MYH11 mutation. The authors review the patient's clinical presentation and management and comprehensively review the literature on this topic.

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Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD

Cited by 142 publications

References 33 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

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

Rapid de novo aneurysm formation after clipping of a ruptured middle cerebral artery aneurysm in an infant with an MYH11 mutation

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