Identification and localization of TBX5 transcription factor during human cardiac morphogenesis

Hatcher, Cathy J.; Goldstein, Martin; Mah, Caroline S.; Delia, C. Susan; Basson, Craig T.

doi:10.1002/1097-0177(200009)219:1<90::aid-dvdy1033>3.0.co;2-l

Cited by 86 publications

(45 citation statements)

References 18 publications

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“…Previous work demonstrating high levels of Tbx5 expression in both atria and the left ventricle and low levels in the right ventricle was confirmed (data not shown) (Bruneau et al, 1999;Hatcher et al, 2000). Abundant Tbx5 expression was also observed in rings surrounding both the tricuspid annulus and mitral annulus in the atrioventricular canal (Fig.…”

Section: Resultssupporting

confidence: 65%

The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system

et al. 2004

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haploinsufficiency caused patterning defects of both the left and right ventricular bundle branches, including absence or severe abnormalities of the right bundle branch. Absence of the right bundle branch correlated with rightbundle-branch block by ECG. Deficiencies in the gap junction protein gene connexin 40 (Cx40), a downstream target of Tbx5, did not account for morphologic conduction system defects in Tbx5 del/+ mice. We conclude that Tbx5 is required for Cx40-independent patterning of the cardiac conduction system, and suggest that the electrophysiologic defects in Holt-Oram syndrome reflect a developmental abnormality of the conduction system.

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Section: Resultssupporting

confidence: 65%

The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system

et al. 2004

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“…To determine heart rate variability (HRV), 300 s of ECG data were acquired before biopsy and analyzed (13). Necropsy tissues were formalin-fixed and processed for microscopy (14). Rabbit polyclonal anti-R1␣ antibody (Chemicon) was used for immunohistochemistry with antigen retrieval and LSAB2 detection (Dako).…”

Section: Methodsmentioning

confidence: 99%

Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Veugelers

Wilkes

Burton

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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144

122

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Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1α of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a +/– mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a +/– mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a +/– mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation.

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“…The normal cellular localisation of the TBX5 protein is in the nucleus in cardiomyocytes. 28 Fan et al 29,30 analysed various missense mutations and in frame deletions and described their possible pathogenetic mechanisms as either: (a) abnormal cellular localisation of mutant TBX5 protein or (b) altered interactions with cardiac or limb specific co-factors (eg, NKX2.5, GATA4, Cx40 and SALL4). They showed increased concentrations within the cytoplasm of TBX5 mutant proteins from various missense mutations and one in-frame deletion, providing evidence of altered nuclear localisation.…”

Section: Discussionmentioning

confidence: 99%

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

Patel

Silcock²,

McMullan³

et al. 2012

Eur J Hum Genet

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Holt-Oram syndrome (HOS) is a rare autosomal dominant heart-hand syndrome due to mutations in the TBX5 transcription factor. Affected individuals can have structural cardiac defects and/or conduction abnormalities, and exclusively upper limb defects (typically bilateral, asymmetrical radial ray defects). TBX5 mutations reported include nonsense, missense, splicing mutations and exon deletions. Most result in a null allele and haploinsufficiency, but some impair nuclear localisation of TBX5 protein or disrupt its interaction with co-factors and downstream targets. We present a five generation family of nine affected individuals with an atypical HOS phenotype, consisting of ulnar ray defects (ulnar hypoplasia, short fifth fingers with clinodactyly) and very mild radial ray defects (short thumbs, bowing of the radius and dislocation of the radial head). The cardiac defects seen are those more rarely reported in HOS (atrioventricular septal defect, hypoplastic left heart syndrome, mitral valve disease and pulmonary stenosis). Conduction abnormalities include atrial fibrillation, atrial flutter and sick sinus syndrome. TBX5 mutation screening (exons 3-10) identified no mutations. Array comparative genomic hybridisation (CGH) revealed a 48 kb duplication at 12q24.21, encompassing exons 2-9 of the TBX5 gene, with breakpoints within introns 1-2 and 9-10. The duplication segregates with the phenotype in the family, and is likely to be pathogenic. This is the first known report of an intragenic duplication of TBX5 and its clinical effects; an atypical HOS phenotype. Further functional studies are needed to establish the effects of the duplication and pathogenic mechanism. All typical/atypical HOS cases should be screened for TBX5 exon duplications.

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Identification and localization of TBX5 transcription factor during human cardiac morphogenesis

Cited by 86 publications

References 18 publications

The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system

The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system

Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

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