TBX1
Non syndromic associated CHDs overview
R aortic arch (1, 100%)
Syndromic associated CHDs overview
Interrupted aortic arch (1, 16.7%)
Pulmonary valvar stenosis - congenital (1, 16.7%)
Tetralogy of Fallot (4, 66.7%)
[edit] Synopsis
TBX1 is located on chromosome 22q11.2. Recurrent deletions of this region are found in patients with DiGeorge syndrome/Velocardiofacial syndrome (DGS/VCFS) (OMIM:188400), while duplications and triplications cause the duplication 22q11.2 syndrome (OMIM:608363). TBX1 is considered to be responsible for these syndromes, since mutations in this gene have been identified in patients with a similar phenotype. Polymorphisms in the VEGF promotor region are shown influence the expressivity of the cardiac phenotype associated with DiGeorge Syndrome.
[edit] Mutation screens
Initially mutational analysis of a total of 121 DGS/VCFS patients without 22q11 deletion failed to identify pathogenically significant alterations in TBX1 (Chieffo et al., 1997; Gong et al., 2001). However in 2003, Yagi et al. identified 2 missense and 1 truncation mutation by screening of 10 patients with DGS/VCFS without 22q11 deletion. Subsequently, additional TBX1 mutations were found by Paylor et al., 2006, Zweier et al., 2007 (no CHD) and Torres-Juan et al., 2007. Mutation analysis of the TBX1 gene in isolated, nonsyndromic conotruncal heart defects (CTD) was initially performed by Conti et al., 2003. Mutation analysis of the TBX1 gene in 41 patients affected by nonsyndromic CTDs of the DGS/VCFS subtype (26 Tetralogy of Fallot, 11 Truncus arteriosus and 4 interrupted aortic arch). Besides a few polymorphisms, no pathogenetic variation was found. Recently, Griffin HR et al., 2010 detected three novel variants in 93 individuals with non-syndromic tetralogy of Fallot (ToF). One of these variants decreased transcriptional activity by 40% in a dual luciferase assay. These studies showed that functionally relevant TBX1 variants are present in a small proportion of non-syndromic ToF.
External references for TBX1
Known phenotypes for TBX1
Non-syndromic
Add another phenotype.
Syndromic
Add another phenotype.
Protein interaction partners
Patients reports for TBX1
Translocations
| Region |
References |
OMIM |
Comments
|
Add another translocation.
Mutations in TBX1
| Mutation (DNA)
|
Mutation (peptide)
|
CHD
|
Reference
|
Other features
|
Inheritence
|
Additional info.
|
 c.1399-1428dup30
|
|
Tetralogy of Fallot
|
PMID:19948535
|
Scoliosis, facial asymmetry, upslanting
palpebral fissures, absent PV, isolated
left pulmonary artery
|
Dominant Sporadic
|
 show  hide
| Genetic evidence
|
de novo not present in 185 normal controls
|
| in silico prediction
|
|
| Functional studies
|
Despite normal mRNA levels as revealed by RT-PCR, the transcriptional reporter assay showed severely reduced transcriptional activity of the mutant construct containing the c.1399-1428dup30. Immunofluorescence studies demonstrated aggregation of the protein in the cytoplasma due to the expansion of a polyalanine tract.
|
| Comments
|
|
|
| NM_080646.1:c.928G>A
|
NP_542377.1:p.Gly310Ser
|
Interrupted aortic arch
|
PMID:14585638
|
Sporadic patient with facial dysmorphism (VCFS-like), thymys hypoplasia, parathyroid dysfunction and congenital heart defect (interrupted aortic arch and perimembranous VSD)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/555 normal controls
|
| in silico prediction
|
Missense mutation in T-box domain, which is highly conserved and responsible for DNA binding and is likely important for dimerization of TBX1.
|
| Functional studies
|
Transcriptional reporter assay: in a CMV expression vector containing the complete cDNA of human TBX1 isoform C, the three mutations published by Yagi et al. and the p.194H>Q mutation was introduced. The truncating mutation reported by Yagi et al. (1223delC) showed virtually no activation. The two missense mutations F148Y and G310S, which had behaved similarly to wild type in the assay done by Stoller et al., exhibited a slight but reproducible and statistically significant increase in activation relative to wild-type TBX1C in this assay. The mutation H194Q showed an even larger increase in activation.
|
| Comments
|
|
|
| NM_080646.1(TBX1):c.443T>A
|
NP_542377.1:p.Phe148Tyr
|
Tetralogy of Fallot
|
PMID:14585638
|
Sporadic DGS/VCFS patient with facial dysmorphism (VCFS-like) and CHD (ToF with pulmonic atresia, ASD2 and MAPCAs)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
mother is normal (no paternal DNA available); 0/555 normal controls
|
| in silico prediction
|
Missense mutation in the T-box domain, T-box domain is highly conserved and responsible for DNA binding and is likely important for dimerization of TBX1.
|
| Functional studies
|
Transcriptional reporter assay: in a CMV expression vector containing the complete cDNA of human TBX1 isoform C, the three mutations published by Yagi et al. and the p.194H>Q mutation was introduced. The truncating mutation reported by Yagi et al. (1223delC) showed virtually no activation. The two missense mutations F148Y and G310S, which had behaved similarly to wild type in the assay done by Stoller et al., exhibited a slight but reproducible and statistically significant increase in activation relative to wild-type TBX1C in this assay. The mutation H194Q showed an even larger increase in activation.
|
| Comments
|
|
|
| NM_080646:c.1223delC
|
NP_542377:p.51>Xfs
|
Tetralogy of Fallot
|
PMID:14585638
|
Familial DGS/VCFS: proband with dysmorphism of the nose, CHD (ToF and RAA), and hypoplastic thymus. His sister presented with atypical VCFS facies and velopharyngeal insufficiency, his mother with VCFS facies, velopharyngeal insufficiency and parathyroid dysfunction.
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 3/3 affected members (CHD in 1/3); 0/555 normal controls
|
| in silico prediction
|
Truncated TBX1 protein remains as the DNA binding motif but does not contain the C-terminal region, including the putative activator and repressor domains.
|
| Functional studies
|
Transcriptional reporter assay: in a CMV expression vector containing the complete cDNA of human TBX1 isoform C, the three mutations published by Yagi et al. and the p.194H>Q mutation was introduced. The truncating mutation reported by Yagi et al. (1223delC) showed virtually no activation. The two missense mutations F148Y and G310S, which had behaved similarly to wild type in the assay done by Stoller et al., exhibited a slight but reproducible and statistically significant increase in activation relative to wild-type TBX1C in this assay. The mutation H194Q showed an even larger increase in activation.
|
| Comments
|
|
|
| c.1320–1342del23bp
|
frameshift mutation
|
Tetralogy of Fallot
|
PMID:16684884
|
Familial DGS/VCFS: proband with facial appearance of VCFS and hypernasal speech, but no CHD. Both sons had appearance of VCFS, CHD and diagnosis of Asperger syndrome. Deceased daughter with VCFS appearance (no further data available).
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 3/3 affected members (1/3 no CHD, 1/3 PS, 1/3 ToF); no DNA available from deceased family member; 0/716 normal controls
|
| in silico prediction
|
The frameshift created by 1320–1342del23bp starts at codon 440 in the C-terminus of the TBX1 protein and extends the protein from 504 to 616 amino acids. Although the mutation does not affect the T-box, it disrupts the central domain (amino acids 439–448) of a highly conserved nuclear localization signal (NLS) of the wild-type TBX1 protein, where it changes the conserved residues PYP to WPR Paylor et al., 2006.
|
| Functional studies
|
Paylor et al. tested the ability of human TBX1 cDNA carrying the 1320–1342del23bp mutation to localize to the nucleus and to transactivate a T-box-binding element construct in a tissue culture system. Immunocytochemical investigation of transfected cells.TBX1 is a transcriptional activator that can induce expression of a CAT-reporter protein under the control of a Brachyury consensus binding site sequence, 1T-CAT. Using the same experimental system, Paylor et al. found that wild-type TBX1 activated the CAT reporter, whereas the mutant construct 1320–1342del23bp did not. These data suggest that this mutation is a null mutation and that their disease phenotype results from TBX1 haploinsufficiency.
|
| Comments
|
|
|
| c.1320–1342del23bp
|
frameshift mutation
|
Pulmonary valvar stenosis - congenital
|
PMID:16684884
|
Familial DGS/VCFS: proband with facial appearance of VCFS and hypernasal speech, but no CHD. Both sons had appearance of VCFS, CHD and diagnosis of Asperger syndrome. Deceased daughter with VCFS appearance (no further data available).
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 3/3 affected members (1/3 no CHD, 1/3 PS, 1/3 ToF); no DNA available from deceased family member; 0/716 normal controls
|
| in silico prediction
|
The frameshift created by 1320–1342del23bp starts at codon 440 in the C-terminus of the TBX1 protein and extends the protein from 504 to 616 amino acids. Although the mutation does not affect the T-box, it disrupts the central domain (amino acids 439–448) of a highly conserved nuclear localization signal (NLS) of the wild-type TBX1 protein, where it changes the conserved residues PYP to WPR Paylor et al., 2006.
|
| Functional studies
|
Paylor et al. tested the ability of human TBX1 cDNA carrying the 1320–1342del23bp mutation to localize to the nucleus and to transactivate a T-box-binding element construct in a tissue culture system. Immunocytochemical investigation of transfected cells.TBX1 is a transcriptional activator that can induce expression of a CAT-reporter protein under the control of a Brachyury consensus binding site sequence, 1T-CAT. Using the same experimental system, Paylor et al. found that wild-type TBX1 activated the CAT reporter, whereas the mutant construct 1320–1342del23bp did not. These data suggest that this mutation is a null mutation and that their disease phenotype results from TBX1 haploinsufficiency.
|
| Comments
|
|
|
Representation of protein TBX1
Heart expression domain of TBX1
Stage 9.5 embryonic days
Add a new domain where gene TBX1 is expressed
Associated CHDs found by automated text mining
- Aortic arch abnormality (09.28.00) (sig = 6.859)
[ show ]
[ hide ]
- Tetralogy of Fallot (01.01.01) (sig = 0.821)
[ show ]
[ hide ]
See complete results on Genopedia (including non CHD)
Heart defects
- 4-31 congenital anomalies of the heart
This page contributors
- Jeroen Breckpot - CME Leuven (Belgium) (association, mutation, study, Free text)
ensembl: ENSG00000184058
OMIM: 602054
Search miRBase for TBX1
Expression patterns from 4DXPress: TBX1
MGI: MGI:98493
ZFIN: ZDB-GENE-030805-5
Wikipedia: TBX1
Search Wikiproteins: TBX1
Search Genetic Association Database: TBX1
Search GeneTests: TBX1
CHeartED:
