DiGeorge subtypes of nonsyndromic conotruncal defects: evidence against a major role of TBX1 Gene

Conti, Emanuela; Grifone, Nicoletta; Sárközy, Anna; Tandoi, Caterina; Marino, Bruno; Digilio, María Cristina; Mingarelli, Rita; Pizzuti, Antonio; Dallapiccola, Bruno

doi:10.1038/sj.ejhg.5200956

Cited by 44 publications

(34 citation statements)

References 19 publications

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“…However, no pathogenic mutations or sequence variants of TBX1 were detected in the patients and healthy controls. While this is in agreement with the report by Conti et al [1], it is also in contrast with a few studies that have documented either mutations or polymorphisms in TBX1 associated with isolated CTA [2-5]. Our results, though negative, provide corroborative evidence that TBX1 mutations may not be associated with CTA in the selected pediatric population.…”

supporting

confidence: 92%

Mutation Analysis of TBX1 in Children with Conotruncal Heart Anomalies

et al. 2015

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To the Editor: Conotruncal heart anomalies (CTA) are structural malformations involving the outflow tract. While the exact incidence of CTA in India is not known, it remains the most common type of structural birth defect with a major impact on pediatric morbidity and mortality. While most CTA are sporadic, a few are associated with genetic syndromes; the 22q11 deletion syndrome (22q11.2DS) being the predominate one. The CTA related to the 22q11.2DS are usually associated with a common 3 Mb or 1.5 Mb proximally deleted region, both of which include the TBX1 gene. However, mutations of the TBX1 gene have also been reported in patients who do not have the 22q11.2 deletion but present with CTA. The TBX1 gene encodes a transcription factor of the T-box family and mouse models have demonstrated that TBX1 haploinsufficiency cause cardiac outflow tract lesions.In a case-control study involving 96 cases of CTA and 100 control subjects, ranging in age from newborns to 18 y, fluorescence in situ hybridization (FISH) was performed on the cases to rule out the 22q11.2 μ-deletion. Further, screening for mutations or sequence variants in four exons of the T-box region, which showed 98 % homology to mouse TBX1, was performed using Sanger sequencing.One out of the 96 cases with CTA (1 %) was found to have the 22q11.2 μ-deletion. However, no pathogenic mutations or sequence variants of TBX1 were detected in the patients and healthy controls. While this is in agreement with the report by Conti et al. [1], it is also in contrast with a few studies that have documented either mutations or polymorphisms in TBX1 associated with isolated CTA [2-5]. Our results, though negative, provide corroborative evidence that TBX1 mutations may not be associated with CTA in the selected pediatric population.

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supporting

confidence: 92%

Mutation Analysis of TBX1 in Children with Conotruncal Heart Anomalies

et al. 2015

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“…47 Additional neighboring genes may modify Tbx1 function or may independently cause PTA. 48,49 The developmental mechanisms of truncal septation have been extensively studied and are well reviewed elsewhere. 50 This structure is key to the proper formation of the heart and likely related to many forms of congenital heart disease.…”

Section: Atrioventricular Canalmentioning

confidence: 99%

Development Gone Awry

Gruber

Epstein

2004

Circulation Research

124

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Abstract-Significant advances in the understanding of the molecular and genetic basis of congenital heart disease have emerged from gene inactivation studies in mice and from human genetic investigations. However, the ability to utilize information gleaned from animal models to inform clinical care of patients depends on an accurate anatomic analysis and presentation in terms that are meaningful to the clinical pediatric cardiologist. Likewise, the enormous depth and breadth of accumulated clinical experience can inform the developmental biologist and can highlight the importance and interrelationships of particular phenotypes. The explosion of potentially informative genetic tools demands that basic scientists and clinicians concerned with congenital cardiac disease enhance the ongoing bidirectional dialogue. In some cases, categories of congenital disease familiar to clinicians are not recognized by developmental biologists, and mechanisms accepted by the biologist seem inconsistent with clinical experience. In this review, we summarize some of the more clinically significant forms of congenital heart disease, and we highlight relevant genetic and developmental pathways. Key Words: congenital heart disease Ⅲ developmental biology Ⅲ animal models C ongenital heart disease (CHD) affects over 1 out of every 100 live births 1,2 and is responsible for the vast majority of prenatal losses. Additionally, 3 per 1000 live births will require an intervention (either catheter-based or surgical) during the first year of life. Despite the importance of this devastating complex of diseases, the causes are largely unknown. What are the obstacles to unraveling the molecular controls of heart morphogenesis? A confluence of recent advances suggests that we are in the midst of a period of significant discovery that will reshape our understanding of congenital cardiac disorders. These advances include the description of an increasing number of gene-targeted mouse models of human cardiac disease, the availability of nearly complete genome sequence for multiple organisms, and increasingly sophisticated bioinformatics tools with which to utilize this data. In addition, the rapidly expanding single nucleotide polymorphism density map will soon make whole genome scans for the genetic causes of rare diseases more fruitful. Once specific causative genes are identified or implicated, the analysis of gene function and the mechanisms underlying the development of cardiovascular disorders can be analyzed in animal models. The manipulation of gene expression is now possible not only in mouse models, where homolo-

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“…However, approximately 10% of DGS/ VCFS cases have no detectable deletion of chromosome 22q11 or 10p13 (Gong et al, 2001;Conti et al, 2003). Screens for point mutations of TBX1 in such cases have been largely negative, but three Japanese cases have been described (Yagi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

Roberts¹,

Ivins²,

James³

et al. 2005

Developmental Dynamics

104

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Both Tbx1 and retinoic acid (RA) are key players in embryonic pharyngeal development; loss of Tbx1 produces DiGeorge syndrome-like phenotypes in mouse models as does disruption of retinoic acid homeostasis. We have demonstrated that perturbation of retinoic acid levels in the avian embryo produces altered Tbx1 expression. In vitamin A-deficient quails, which lack endogenous retinoic acid, Tbx1 expression patterns were disrupted early in development and expression was subsequently lost in all tissues. "Gain-of-function" experiments where RA-soaked beads were grafted into the pharyngeal region produced localized down-regulation of Tbx1 expression. In these embryos, analysis of Shh and Foxa2, upstream control factors for Tbx1, suggested that the effect of RA was independent of this regulatory pathway. Real-time polymerase chain reaction analysis of retinoic acid-treated P19 cells showed a dosedependent repression of Tbx1 by retinoic acid. Repression of Tbx1 transcript levels was first evident after 8 -12 hr in culture in the presence of retinoic acid, and to achieve the highest levels of repression, de novo protein synthesis was required. Developmental Dynamics 232:928 -938, 2005.

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DiGeorge subtypes of nonsyndromic conotruncal defects: evidence against a major role of TBX1 Gene

Cited by 44 publications

References 19 publications

Mutation Analysis of TBX1 in Children with Conotruncal Heart Anomalies

Mutation Analysis of TBX1 in Children with Conotruncal Heart Anomalies

Development Gone Awry

Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro

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