Mouse and Human CRKL Is Dosage Sensitive for Cardiac Outflow Tract Formation

Racedo, Silvia E.; McDonald‐McGinn, Donna M.; Chung, Jonathan; Goldmuntz, Elizabeth; Zackai, Elaine H.; Emanuel, Beverly S.; Zhou, Bin; Funke, Birgit; Morrow, Bernice E.

doi:10.1016/j.ajhg.2014.12.025

Cited by 59 publications

(50 citation statements)

References 46 publications

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“…More generally, our observations support the idea that a single primary genetic lesion can result in a range of OFT defects, which in clinical practice are often considered discrete entities (Dorfman and Geva, 2006;Johnson, 2010). Our data also support the idea that complex alignment phenotypes might form a continuous spectrum of related OFT alignment disorders, as others have also proposed based on observations from other mouse genetic models, particularly for Tbx1 and related pathways (Brown et al, 2004;Racedo et al, 2015;Rana et al, 2014;Vincentz et al, 2005).…”

Section: Results and Discussion Mef2c Is Required For Proper Oft Aligsupporting

confidence: 77%

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

et al. 2016

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Congenital heart defects are the most common birth defects in humans, and defects that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF) gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, the gene that encodes the Nodal co-receptor Cripto, as a direct transcriptional target of MEF2C in the outflow tract via an AHF-restricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may be an embryological spectrum rather than distinct anomalies.

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Section: Results and Discussion Mef2c Is Required For Proper Oft Aligsupporting

confidence: 77%

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

et al. 2016

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“…Zhao et al [2013] reported on a cohort specifically with cardiac defects, and identified a single individual with a central deletion, but the types of cardiac defects are not specified. In Racedo et al [2015], 8/20 B-D deletion subjects and 1/5 C-D deletion subjects had cardiac defects. These included conotruncal defects in 4/25, TOF in 3/25, interrupted aortic arch in 1/25, VSD in 4/25, and atrial septal defect (ASD) in 2/25.…”

Section: Central Deletions (B-d C-d)mentioning

confidence: 99%

“…Of those, sufficient clinical information was provided for 23, resulting in a total of 68 individuals with clinical information ( table 1 ). The study by Racedo et al [2015] only examined cardiac features of 25 individuals with central deletion, so that total is only included in the cardiac category in table 1 , and those 25 are not included in the 45 reported individuals. Seven of the 31 individuals reported from our lab had follow-up studies performed, and 4 deletions were de novo, 2 were familial and 1 unknown.…”

Section: Central Deletions (B-d C-d)mentioning

confidence: 99%

“…Deletions of more distal regions have also been reported extensively, and many of those individuals were referred for suspicion of DGS, highlighting the similarity of phenotypic features for these CNVs [Kurahashi et al, 1996;Rauch et al, 1999Rauch et al, , 2005Saitta et al, 1999;Shaikh et al, 2000;Garcia-Miñaur et al, 2002;Wieser et al, 2005;Jackson et al, 2007;Mikhail et al, 2007Mikhail et al, , 2014Ben-Shachar et al, 2008;Jalali et al, 2008;Rødningen et al, 2008;Xu et al, 2008;Lafay-Cousin et al, 2009;Ogilvie et al, 2009;Bruce et al, 2010;Madan et al, 2010;Beddow et al, 2011;Bourdeaut et al, 2011;Eaton et al, 2011;Garavelli et al, 2011;Nik-Zainal et al, 2011;Tan et al, 2011;Toth et al, 2011;Verhoeven et al, 2011;Yu et al, 2011;Breckpot et al, 2012;Pebrel-Richard et al, 2012;Verhagen et al, 2012;Fagerberg et al, 2013;Zhao et al, 2013;Rump et al, 2014;Racedo et al, 2015]. The literature for these other CNVs is not uniform with respect to the designation of particular intervals, and previous reviews have grouped proximal and distal CNVs together [Tan et al, 2010;Yu et al, 2011].…”

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confidence: 99%

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22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features

Burnside

2015

Cytogenet Genome Res

1,441

149

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Chromosome 22q11.21 contains a cluster of low-copy repeats (LCRs), referred to as LCR22A-H, that mediate meiotic non-allelic homologous recombination, resulting in either deletion or duplication of various intervals in the region. The deletion of the DiGeorge/velocardiofacial syndrome interval LCR22A-D is the most common recurrent microdeletion in humans, with an estimated incidence of ∼1:4,000 births. Deletion of other intervals in 22q11.21 have also been described, but the literature is often confusing, as the terms ‘proximal', ‘nested', ‘distal', and ‘atypical' have all been used to describe various of the other intervals. Individuals with deletions tend to have features with widely variable expressivity, even among families. This review concisely delineates each interval and classifies the reported literature accordingly.

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“…Therefore, the etiology underlying CTD requires elucidation. Previous studies have established the important role genetic risk factors serve in the pathogenesis of CTD (10)(11)(12)(13)(14)(15). The 22q11 deletion syndrome (22q11DS), also known as DiGeorge syndrome, is a chromosomal abnormality responsible for ~12% of conotruncal malformations (16)(17)(18)(19)(20)(21).…”

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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Mouse and Human CRKL Is Dosage Sensitive for Cardiac Outflow Tract Formation

Cited by 59 publications

References 46 publications

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features

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

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