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A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects.

ABSTRACT: BACKGROUND: Ostium secundum atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD), and mutations in cardiac transcription factors, including TBX20, were identified as an underlying cause for ASDII. However, very little is known about disease penetrance in families and functional consequences of inherited TBX20 mutations. METHODS: The coding region of TBX20 was directly sequenced in 170 ASDII patients. Functional consequences of one novel mutation were investigated by surface plasmon resonance, CD spectropolarymetry, fluorescence spectrophotometry, luciferase assay and chromatin immunoprecipitation. RESULTS: We found a novel mutation in a highly conserved residue in the T-box DNA binding domain (I121M) segregating with CHD in a three generation kindred. Four mutation carriers revealed cardiac phenotypes in terms of cribriform ASDII, large patent foramen ovale or cardiac valve defects. Interestingly, tertiary hydrophobic interactions within the mutant TBX20 T-box were significantly altered leading to a more dynamic structure of the protein. Moreover, Tbx20-I121M resulted in a significantly enhanced transcriptional activity, which was further increased in the presence of co-transcription factors GATA4/5 and NKX2-5. Occupancy of DNA binding sites on target genes was also increased. CONCLUSIONS: We suggest that TBX20-I121M adopts a more fluid tertiary structure leading to enhanced interactions with cofactors and more stable transcriptional complexes on target DNA sequences. Our data, combined with that of others, suggest that human ASDII may be related to loss-of-function as well as gain-of-function TBX20 mutations.

SUBMITTER: Posch MG

PROVIDER: S-EPMC2981023 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects.

Posch Maximilian G MG Gramlich Michael M Sunde Margaret M Schmitt Katharina R KR Lee Stella H Y SH Richter Silke S Kersten Andrea A Perrot Andreas A Panek Anna N AN Al Khatib Iman H IH Nemer Georges G Mégarbané André A Dietz Rainer R Stiller Brigitte B Berger Felix F Harvey Richard P RP Ozcelik Cemil C

Journal of medical genetics 20090916 4

<h4>Background</h4>Ostium secundum atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD), and mutations in cardiac transcription factors, including TBX20, were identified as an underlying cause for ASDII. However, very little is known about disease penetrance in families and functional consequences of inherited TBX20 mutations.<h4>Methods</h4>The coding region of TBX20 was directly sequenced in 170 ASDII patients. Functional consequences of one novel m ...[more]

PMID: 19762328

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Project description:BackgroundTranscatheter atrial septal defect (ASD) and patent foramen ovale (PFO) closure might have opposite short- and long-term haemodynamic consequences compared with restricted interatrial shunt creation, which recently emerged as a potential treatment modality for patients with heart failure with preserved ejection fraction (HFpEF). Given the opposing approaches of ASD and PFO closure versus shunt creation, we investigated the early and sustained cardiac structural and functional changes following transcatheter ASD or PFO closure.MethodsIn this retrospective study, adult secundum-type ASD and PFO patients with complete echocardiography examinations at baseline and at 1‑day and 1‑year follow-up who also underwent transcatheter closure between 2013 and 2017 at the University Medical Centre Groningen, the Netherlands were included.ResultsThirty-nine patients (mean age 48 ± standard deviation 16 years, 61.5% women) were included. Transcatheter ASD/PFO closure resulted in an early and persistent decrease in right ventricular systolic and diastolic function. Additionally, transcatheter ASD/PFO closure resulted in an early and sustained favourable response of left ventricular (LV) systolic function, but also in deterioration of LV diastolic function with an increase in LV filling pressure (LVFP), as assessed by echocardiography. Age (β = 0.31, p = 0.009) and atrial fibrillation (AF; β = 0.24, p = 0.03) were associated with a sustained increase in LVFP after transcatheter ASD/PFO closure estimated by mean E/e' ratio (i.e. ratio of mitral peak velocity of early filling to diastolic mitral annular velocity). In subgroup analysis, this was similar for ASD and PFO closure.ConclusionOlder patients and patients with AF were predisposed to sustained increases in left-sided filling pressures resembling HFpEF following ASD or PFO closure. Consequently, these findings support the current concept that creating a restricted interatrial shunt might be beneficial, particularly in elderly HFpEF patients with AF.

Project description:ImportanceThe Patent Foramen Ovale (PFO)-Associated Stroke Causal Likelihood classification system combines information regarding noncardiac patient features (vascular risk factors, infarct topography) and PFO features (shunt size and presence of atrial septal aneurysm [ASA]) to classify patients into 3 validated categories of responsiveness to treatment with PFO closure. However, the distinctive associations of shunt size and ASA, alone and in combination, have not been completely delineated.ObjectiveTo evaluate the association of PFO closure with stroke recurrence according to shunt size and/or the presence of an ASA.Design, setting, and participantsPooled individual patient data from 6 randomized clinical trials conducted from February 2000 to October 2017 that compared PFO closure with medical therapy. Patients in North America, Europe, Australia, Brazil, and South Korea with PFO-associated stroke were included. Analysis was completed in January 2022.ExposuresTranscatheter PFO closure plus antithrombotic therapy vs antithrombotic therapy alone, stratified into 4 groups based on the combination of 2 features: small vs large PFO shunt size and the presence or absence of an ASA.Main outcomes and measuresRecurrent ischemic stroke.ResultsA total of 121 recurrent ischemic strokes occurred in the pooled 3740 patients (mean [SD] age, 45 [10] years; 1682 [45%] female) during a median (IQR) follow-up of 57 (23.7-63.8) months. Treatment with PFO closure was associated with reduced risk for recurrent ischemic stroke (adjusted hazard ratio [aHR], 0.41 [95% CI, 0.28-0.60]; P < .001). The reduction in hazard for recurrent stroke was greater for patients with both a large shunt and an ASA (aHR, 0.15 [95% CI, 0.06-0.35]) than for large shunt without ASA (aHR, 0.27 [95% CI, 0.14-0.56]), small shunt with ASA (aHR, 0.36 [95% CI, 0.17-0.78]), and small shunt without ASA (aHR, 0.68 [95% CI, 0.41-1.13]) (interaction P = .02). At 2 years, the absolute risk reduction of recurrent stroke was greater (5.5% [95% CI, 2.7-8.3]) in patients with large shunt and ASA than for patients in the other 3 categories (1.0% for all).Conclusions and relevancePatients with both a large shunt and an ASA showed a substantially greater beneficial association with PFO closure than patients with large shunt alone, patients with small shunt and ASA, and patients with neither large shunt nor ASA. These findings, combined with other patient features, may inform shared patient-clinician decision-making.

Project description:IntroductionAtrial Septal Defect/Patent Foramen Ovale (ASD/PFO) occlusion is performed to prevent paradoxical embolism and reduce the risk of recurrent ischemic stroke. Left atrial appendage (LAA) closure is used as an alternative to medical therapy of non-valvular atrial fibrillation for prevention of stroke. Multiple studies have examined performing LAA and ASD/PFO occlusion. However, the feasibility and safety of combined occlusion of the left atrial appendage and ASD/PFO are not clear, furthermore, these studies are limited by their small sample sizes and retrospective analysis. In this study, we aimed to systematically review and meta-analyze the feasibility and safety of combining left atrial appendage and ASD/PFO closure.MethodsPubMed, Web of Science, CNKI, Cochrane Library, Embase, and WanFang database were searched up to April 2022 to identify peer-reviewed human studies on assessing the feasibility, safety, and efficacy of combining left atrial appendage and ASD/PFO closure. The primary outcome was calculated: procedural feasibility outcome and procedural safety outcome.ResultsA total of 10 articles, including 340 patients from multiple countries, were included in the analysis. The principal findings of our study are: compared with single LAA closure, (i) combining PFO/ASD occlusion and LAA closure had similar procedural success proportion (98.43%, 95% CI: 96.67-100.00%), (ii) similar safety event incidences developed (1.67%, 95% CI: 0.24-3.92%), subgroup analyzed safety event incidences in death was 0.00 (95% CI: 0.00-0.33%), cardiac tamponade was 0.87% (95% CI: 0.00-2.77%), device embolization was 0.00 (95% CI: 0.00-0.60%), major bleeding was 0.00 (95% CI: 0.00-0.33%), stroke was 0.00 (95% CI: 0.00-0.02%).ConclusionAlthough this systematic review and meta-analysis demonstrate the technical feasibility and safety of combining closure of PFO/ASD and LAA, further studies of sufficient sample size, long-term follow-up, and rigor endpoint criteria are yet needed to fully evaluate this combination procedure for its role in clinical outcomes.

Project description:Patent foramen ovale (PFO)-related stroke is increasingly recognized as an important etiology of ischemic embolic stroke-accounting for up to 50% of strokes previously considered 'cryptogenic' or with an unknown mechanism. As a 'back door to the brain,' PFO can allow venous clots to enter arterial circulation via interatrial right-to-left shunting, potentially resulting in ischemic stroke. We observe that clinically, PFO-related stroke affects women of childbearing age, and that pregnancy-owing to major changes in hemocoagulative, hormonal, and cardiovascular parameters-can enhance stroke risks. However, no systematic study has been performed and little is known regarding complications, pregnancy outcomes and treatment for PFO-related stroke during pregnancy. To identify and characterize the complications and clinical outcomes related to PFOs during pregnancy, we performed a literature review and analysis from all reported cases of pregnancy with PFO-related complications in the medical literature from 1970 to 2015. We find that during pregnancy and post-partum, PFO is associated with complications affecting multiple organs, including the brain, heart and lung. The three principal complications reported are stroke, pulmonary emboli and myocardial infarction. In contrast to other pregnancy-related stroke etiologies, which peak during later pregnancy and postpartum, PFO-related stroke peaks during early pregnancy (first and second trimester-60%), and most patients had good neurological outcome (77%). In patients with PFO with recurrent stroke during pregnancy, additional key factors include high-risk PFO morphology (atrial septal aneurysm), larger right-to-left shunt, multiple gestation and concurrent hypercoagulability. Compared to strokes of other etiologies during pregnancy, most PFO stroke patients experienced uneventful delivery (93%) of healthy babies with a good clinical outcome. We conclude with recommended clinical treatment strategies for pregnant patients with PFO suggested by the data from these cases, and the clinical experience of our Cardio-Neurology Clinic.

Dataset Information

A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects.

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A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects.

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