{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T09:28:00Z","timestamp":1740130080277,"version":"3.37.3"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T00:00:00Z","timestamp":1665705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL165270","HL150589","HL143067"],"award-info":[{"award-number":["HL165270","HL150589","HL143067"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Haploinsufficiency of TGF-beta-activated kinase 1 (MAP3K7) binding protein 2 (TAB2) has been associated with congenital heart disease and more recently multiorgan structural abnormalities. Missense variant represents a major proportion of non-synonymous TAB2 variants reported in gnomAD (295\/576) and Clinvar (16\/73), most of which are variants of uncertain significance (VUSs). However, interpretation of TAB2 missense variants remains challenging because of lack of functional assays. To address this issue, we established a cell-based luciferase assay that enables high-throughput screening of TAB2 variants to assess the functional consequence for predicting variant pathogenicity. Using this platform, we screened 47 TAB2 variants including five pathogenic controls and one benign control, and the results showed that the transcriptional activity of activator protein 1 (AP-1) but not nuclear factor kappa B predicts the TAB2 variant pathogenicity. This assay provides accurate functional readout for both loss-of-function (LOF) and gain-of-function variants, which are associated with distinct phenotypes. In all, 22 out of 32 tested VUSs were reclassified. Genotype\u2013Phenotype association showed that most patients with partial LOF variants do not exhibit congenital heart disease but high frequency of developmental delay, hypotonia and dysmorphic features, which suggests that genetic testing for TAB2 is needed for a broader spectrum of patients with more diverse phenotypes. Molecular modeling with Npl4 zinc finger (NZF) domain variants revealed that the stability of the NZF domain in TAB2 protein is crucial for AP-1 activation. In conclusion, we developed a highly effective functional assay for TAB2 variant prediction and interpretation.<\/jats:p>","DOI":"10.1093\/hmg\/ddac252","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T04:26:23Z","timestamp":1665721583000},"page":"959-970","source":"Crossref","is-referenced-by-count":0,"title":["Assigning pathogenicity for TAB2 variants using a novel scalable functional assay and expanding TAB2 disease spectrum"],"prefix":"10.1093","volume":"32","author":[{"given":"Weiyi","family":"Xu","sequence":"first","affiliation":[{"name":"Baylor College of Medicine Department of Molecular and Human Genetics, , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Graves","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Department of Molecular and Human Genetics, , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Weisz-Hubshman","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Department of Molecular and Human Genetics, , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lamees","family":"Hegazy","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine and University of Health Sciences & Pharmacy Center for Clinical Pharmacology, , St. Louis, MO , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Magyar","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Department of Molecular and Human Genetics, , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zian","family":"Liu","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Department of Molecular Physiology and Biophysics, , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleni","family":"Nasiotis","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Department of Molecular and Human Genetics, , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md Abul Hassan","family":"Samee","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Department of Molecular Physiology and Biophysics, , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Burris","sequence":"additional","affiliation":[{"name":"University of Florida Genetics Institute, , Gainesville, FL , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seema","family":"Lalani","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Department of Molecular and Human Genetics, , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6320-1318","authenticated-orcid":false,"given":"Lilei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Department of Molecular and Human Genetics, , Houston, TX , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"key":"2023030719030190900_","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.ajhg.2010.04.011","article-title":"Haploinsufficiency of TAB2 causes congenital heart defects in humans","volume":"86","author":"Thienpont","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"2023030719030190900_","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1038\/s41431-021-00948-0","article-title":"TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility","volume":"29","author":"Engwerda","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"2023030719030190900_","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1002\/ajmg.a.38254","article-title":"6q25.1 (TAB2) microdeletion syndrome: congenital heart defects and cardiomyopathy","volume":"173","author":"Cheng","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"2023030719030190900_","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/cge.13032","article-title":"A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations","volume":"93","author":"Ritelli","year":"2018","journal-title":"Clin. Genet."},{"key":"2023030719030190900_","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12872-019-01322-1","article-title":"A novel TAB2 nonsense mutation (p.S149X) causing autosomal dominant congenital heart defects: a case report of a Chinese family","volume":"20","author":"Chen","year":"2020","journal-title":"BMC Cardiovasc. Disord."},{"key":"2023030719030190900_","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.ajhg.2016.05.024","article-title":"Mutations in MAP3K7 that alter the activity of the TAK1 signaling complex cause frontometaphyseal dysplasia","volume":"99","author":"Wade","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"2023030719030190900_","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1002\/ajmg.a.38267","article-title":"Autosomal dominant frontometaphyseal dysplasia: delineation of the clinical phenotype","volume":"173","author":"Wade","year":"2017","journal-title":"Am. J. Med. Genet. 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