Protein molecular modeling techniques investigating novel <i><scp>TAB</scp>2</i> variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family

Caulfield, Thomas R.; Richter, John E.; Brown, Emily; Mohammad, Ahmed N.; Judge, Daniel P.; Atwal, Paldeep S.

doi:10.1002/mgg3.401

Cited by 18 publications

(27 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, no abnormality in the connective tissues was observed in the patients in our study. The family carrying the TAB2 p.R347X nonsense mutation did not show any connective tissue disorders either [19]. These findings suggest clinical heterogeneity of extracardiac tissues in Fig.…”

Section: Discussionmentioning

confidence: 57%

“…WES of a male child with polyvalvular syndrome revealed a c.1491 T > A nonsense mutation (p.Y497X) in TAB2 [18]. Pulmonary artery aneurysm, moderate mitral regurgitation, and mild tricuspid regurgitation were discovered in a family with a c.1039 C > T nonsense (p.R347X) TAB2 mutation [19]. A c.1398dupT mutation in TAB2 was confirmed in a family with polyvalvular heart disease [14].…”

Section: Discussionmentioning

confidence: 83%

See 1 more Smart Citation

A novel TAB2 nonsense mutation (p.S149X) causing autosomal dominant congenital heart defects: a case report of a Chinese family

Chen

Yuan

Xie

et al. 2020

BMC Cardiovasc Disord

View full text Add to dashboard Cite

Background: TAB2 is an activator of MAP 3 K7/TAK1, which is required for the IL-1 induced signal pathway. Microdeletions encompassing TAB2 have been detected in various patients with congenital heart defects (CHD), indicating that haploinsufficiency of TAB2 causes CHD. To date, seven variants within TAB2 were reported associated with CHD, only two of them are nonsense mutations. Case presentation: Here we describe a three-generation Chinese family that included five CHD patients with heart valvular defects, such as mitral or tricuspid valves prolapse or regurgitation, and aortic valve stenosis or regurgitation. Our proband was a pregnant woman presenting with mitral, tricuspid, and aortic defects; her first child experienced sudden cardiac death at the age of 2 years. Whole-exome sequencing of the proband revealed a novel nonsense variant in TAB2 (c.C446G, p.S149X), which results in the elimination of the majority of C-terminal amino acids of TAB2, including the critical TAK1-binding domain. The variant was identified in five affected patients but not in the eight unaffected family members using Sanger sequencing and was classified as "pathogenic" according to the latest recommendation on sequence variants laid out by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Conclusion: We described a family with CHD caused by a novel TAB2 nonsense mutation. Our study broadens the mutation spectrum of TAB2; to the best of our knowledge, this is the first report of a pathogenic mutation within TAB2 in a Chinese population.

show abstract

Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 83%

A novel TAB2 nonsense mutation (p.S149X) causing autosomal dominant congenital heart defects: a case report of a Chinese family

Chen

Yuan

Xie

et al. 2020

BMC Cardiovasc Disord

View full text Add to dashboard Cite

show abstract

“…Since this initial report, additional patients have been reported to have single nucleotide variants (SNV) in TAB2. [6][7][8][9][10][11][12][13] The clinical presentation has primarily been reported as nonsyndromic CHD, including valvular and cardiac outflow tract structural abnormalities. However, other clinical features have sometimes been noted including facial dysmorphism, skeletal and connective tissue defects.…”

Section: Introductionmentioning

confidence: 99%

TAB2 variants cause cardiovascular heart disease, connective tissue disorder, and developmental delay

et al. 2021

View full text Add to dashboard Cite

Congenital heart defects (CHD) are the most commonly occurring birth defect and can occur in isolation or with additional clinical features comprising a genetic syndrome. Autosomal dominant variants in TAB2 are recognized by the American Heart Association as causing nonsyndromic CHD, however, emerging data point to additional, extra-cardiac features associated with TAB2 variants. We identified 15 newly reported individuals with pathogenic TAB2 variants and reviewed an additional 24 subjects with TAB2 variants in the literature. Analysis showed 64% (25/39) of

show abstract

“…In humans, TAB2 haploinsufficiency has been proposed as the master molecular finding in the recurrent 6q25.1 microdeletion syndrome, which is characterized by cardiomyopathy, congenital heart defect, and satellite features (Cheng et al, 2017). In addition, rare TAB2 point variants have been associated with frontometaphyseal dysplasia type 3 (Wade et al, 2016) and isolated cardiomyopathy or congenital heart defects (Caulfield et al, 2018;Thienpont et al, 2010).…”

mentioning

confidence: 99%

TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis

et al. 2019

View full text Add to dashboard Cite

Transforming growth factor β‐activated kinase 1 (TAK1) mediates multiple biological processes through the nuclear factor κ‐light‐chain‐enhancer of activated B cells (NF‐κB) and the mitogen‐activated protein kinase (MAPK) signaling pathways. TAK1 activation is tightly regulated by its binding partners (TABs). In particular, binding with TAB2 is crucial for cardiovascular development and extracellular matrix (ECM) homeostasis. In our previous work, we reported a novel multisystem disorder associated with the heterozygous TAB2 c.1398dup variant. Here, we dissect the functional effects of this variant in order to understand its molecular pathogenesis. We demonstrate that TAB2 c.1398dup considerably undergoes to nonsense‐mediated messenger RNA decay and encodes a truncated protein that loses its ability to bind TAK1. We also show an alteration of the TAK1 autophosphorylation status and of selected downstream signaling pathways in patients’ fibroblasts. Immunofluorescence analyses and ECM‐related polymerase chain reaction‐array panels highlight that patient fibroblasts display ECM disorganization and altered expression of selected ECM components and collagen‐related pathways. In conclusion, we deeply dissect the molecular pathogenesis of the TAB2 c.1398dup variant and show that the resulting phenotype is well explained by TAB2 loss‐of‐function. Our data also offer initial insights on the ECM homeostasis impairment as a molecular mechanism probably underlying a multisystem disorder linked to TAB2.

show abstract

Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family

Cited by 18 publications

References 28 publications

A novel TAB2 nonsense mutation (p.S149X) causing autosomal dominant congenital heart defects: a case report of a Chinese family

A novel TAB2 nonsense mutation (p.S149X) causing autosomal dominant congenital heart defects: a case report of a Chinese family

TAB2 variants cause cardiovascular heart disease, connective tissue disorder, and developmental delay

TAB2 c.1398dup variant leads to haploinsufficiency and impairs extracellular matrix homeostasis

Contact Info

Product

Resources

About