Understanding the Role of Tbx1 as a Candidate Gene for 22q11.2 Deletion Syndrome

Gao, Shan; Li, Xiao; Amendt, Brad A.

doi:10.1007/s11882-013-0384-6

Cited by 59 publications

(42 citation statements)

References 82 publications

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“…[47][48][49] Additionally, the 22q11 deletion syndromes, including Velocardiofacial syndrome and DiGeorge syndrome, in which patients present with heart defects, hypoplastic thymus, and mild craniofacial defects, are also thought to be partially attributable to defects in NCCs. 71,72 p53 suppression by genetic ablation or pharmacological inhibition can partially rescue phenotypes of Tbx1 heterozygous mice, which develop features of DiGeorge syndrome, including cardiac outflow tract defects and thymic aplasia. 73 Furthermore, p53 has been reported to contribute to NCC defects in Treacher Collins syndrome, where p53 activation in Tcof1 C/¡ embryos triggers apoptosis of neuroepithelial cells and deficiencies in the formation of migrating cranial NCCs, culminating in craniofacial malformations.…”

Section: The Role Of P53 In Other Diseasesmentioning

confidence: 99%

Guilty as CHARGED: p53's expanding role in disease

Nostrand¹,

Attardi²

2014

Cell Cycle

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Section: The Role Of P53 In Other Diseasesmentioning

confidence: 99%

Guilty as CHARGED: p53's expanding role in disease

Nostrand¹,

Attardi²

2014

Cell Cycle

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“…It serves a crucial role in cardiovascular morphogenesis, particularly in elongating the cardiac tube at the anterior pole and maintaining the proliferation of mesenchymal precursor cells for the formation of a myocardialized and septated outflow tract (45). The expression of TBX1 varies spatiotemporally in the tissues that form the pharyngeal apparatus, which develops into the heart during embryogenesis (46). Genetic studies in mice have demonstrated that TBX1 expression during embryogenesis requires specific regulation and in patients with 22q11DS, it has been observed that increases or decreases in TBX1 transcript levels may result in developmental malformations (46)(47)(48)(49).…”

Section: Introductionmentioning

confidence: 99%

“…The expression of TBX1 varies spatiotemporally in the tissues that form the pharyngeal apparatus, which develops into the heart during embryogenesis (46). Genetic studies in mice have demonstrated that TBX1 expression during embryogenesis requires specific regulation and in patients with 22q11DS, it has been observed that increases or decreases in TBX1 transcript levels may result in developmental malformations (46)(47)(48)(49). Furthermore, in vivo studies have identified that TBX1 is a candidate gene for 22q11DS (48)(49)(50).…”

Section: Introductionmentioning

confidence: 99%

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

Zhang

Liu

et al. 2017

Exp Ther Med

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Abstract. Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the TBX1 gene that codes for a T-box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of TBX1 in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified TBX1 sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic in silico. Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the ANF promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.

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“…Also, 12 additional T-Box1 (TBX1) probes are included in the P324 kit (the P250 kit has only two TBX1 probes) (supplementary on-line material, table 1). TBX1 is one of the most important candidate genes at 22q11.2 concerning physical abnormalities in 22q11DS [30, 31], but it is also associated with psychiatric features like autism spectrum disorders [32] and in mouse models with social interaction problems [33] and autism [34]. …”

Section: Introductionmentioning

confidence: 99%

The use of two different MLPA kits in 22q11.2 deletion syndrome

Evers

Engelen

Houben

et al. 2016

European Journal of Medical Genetics

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22q11.2 deletion syndrome (22q11DS) is one of the most common recurrent copy-number variant disorder, caused by a microdeletion in chromosome band 22q11.2 and occurring with a population prevalence of 1 in 2000. Until today there has been no evidence that the size of the deletion has an influence on the clinical phenotype. Most studies report that 22q11DS is associated with mild or borderline intellectual disability. There are a limited number of reports on 22q11DS subjects with moderate or severe intellectual disability. In this study we describe 63 adult patients with 22q11DS, including 22q11DS patients functioning at a moderate to severe intellectual disabled level. Deletion size was established with an experimental Multiplex ligation-dependent probe amplification (MLPA) mixture (P324) in addition to the commonly used MLPA kit (P250). We compared deletion size with intellectual functioning and presence of psychotic symptoms during life. The use of the experimental MLPA kit gives extra information on deletion size, only when combined with the common MLPA kit. We were able to detect eleven atypical deletions and in two cases the deletion size was shorter than all other “typical ones”. We conclude that the use of the experimental kit P324 gives extra information about the deletion size, but only when used together with the standard P250 kit. We did not found any relation of deletion size with intelligence or presence of psychosis.

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Understanding the Role of Tbx1 as a Candidate Gene for 22q11.2 Deletion Syndrome

Cited by 59 publications

References 82 publications

Guilty as CHARGED: p53's expanding role in disease

Guilty as CHARGED: p53's expanding role in disease

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

The use of two different MLPA kits in 22q11.2 deletion syndrome

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