ALK2 mutation in a patient with Down's syndrome and a congenital heart defect

Joziasse, Irene C.; Smith, K. A.; Chocron, Sonja; Dinther, Maarten van; Guryev, Victor; Smagt, Jasper J. van de; Cuppen, Edwin; Dijke, Peter ten; Mulder, Barbara J.M.; Maslen, Cheryl L.; Reshey, Benjamin; Doevendans, Pieter A.; Bakkers, Jeroen

doi:10.1038/ejhg.2010.224

Cited by 33 publications

(22 citation statements)

References 24 publications

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“…Myocardial “deletion” of BMP4 through use of compound transgenic mice carrying a cardiac-TroponinT-cre (cTnT-cre) allele, a BMP4 tm1 null allele, and a Bmp4 loxp-lacZ allele, also resulted in complete penetrance of the AVSD phenotype 45 . The importance of BMP signaling to atrial and AV septation is also supported by findings in humans as mutations in BMP4 and the BMP receptor Alk2 have been implicated in the etiology of, respectively, atrial septal defects and AVSDs 46–48 .…”

Section: Discussionmentioning

confidence: 75%

Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation

Briggs

Phelps

Brown

et al. 2013

Circulation Research

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Rationale The Dorsal Mesenchymal Protrusion (DMP) is a prong of mesenchyme derived from the Second Heart Field (SHF) located at the venous pole of the developing heart. Recent studies have shown that perturbation of its development is associated with the pathogenesis of atrioventricular septal defect (AVSD). Although the importance of the DMP to AV septation is now established, the molecular and cellular mechanisms underlying its development are far from fully understood. Prior studies have demonstrated that bone morphogenetic protein (BMP) signaling is essential for proper formation of the AV endocardial cushions and the cardiac outflow tract. A role for BMP signaling in regulation of DMP development remained to be elucidated. Objective To determine the role of BMP signaling in DMP development. Methods and Results Conditional deletion of the BMP receptor Alk3 from venous pole SHF cells leads to impaired formation of the DMP and a completely penetrant phenotype of ostium primum defect, a hallmark feature of AVSDs. Analysis of mutants revealed decreased proliferative index of SHF cells and, consequently, reduced number of SHF cells at the cardiac venous pole. In contrast, volume and expression of markers associated with proliferation and active BMP/TGFβ signaling was not significantly altered in the AV cushions of SHF-Alk3 mutants. Conclusions BMP signaling is required for expansion of the SHF-derived DMP progenitor population at the cardiac venous pole. Perturbation of Alk3-mediated BMP signaling from the SHF results in impaired development of the DMP and ostium primum defects.

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Section: Discussionmentioning

confidence: 75%

Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation

Briggs

Phelps

Brown

et al. 2013

Circulation Research

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“…We have previously shown that ALK2 is required and sufficient for endocardial cell EMT in vitro [19] [19, 41] while others have demonstrated that both ALK2 [42] and ALK3 [43, 44] are required for endocardial cell EMT in vivo . In humans, a dominant negative form of ALK2 has been associated in a patient with AVC defects [45] and a second mutant form has been described in a Down’s Syndrome patient with congenital heart defects [46] highlighting the importance of ALK2 signaling in human cardiac cushion morphogenesis. We therefore used a siRNA knockdown approach to test for the requirement of several ALKs downstream of TGFβ2 or BMP-2 stimulated, TGFβR3-mediated endocardial cell EMT.…”

Section: 0 Discussionmentioning

confidence: 99%

Endocardial cell epithelial-mesenchymal transformation requires Type III TGFβ receptor interaction with GIPC

Townsend¹,

Robinson²,

How³

et al. 2012

Cellular Signalling

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An early event in heart valve formation is the epithelial-mesenchymal transformation (EMT) of a subpopulation of endothelial cells in specific regions of the heart tube, the endocardial cushions. The Type III TGFβ receptor (TGFβR3) is required for TGFβ2- or BMP-2-stimulated EMT in atrioventricular endocardial cushion (AVC) explants in vitro but the mediators downstream of TGFβR3 are not well described. Using AVC and ventricular explants as an in vitro assay, we found an absolute requirement for specific TGFβR3 cytoplasmic residues, GAIP-interacting protein, C terminus (GIPC), and specific Activin Receptor-Like Kinases (ALK)s for TGFβR3-mediated EMT when stimulated by TGFβ2 or BMP-2. The introduction of TGFβR3 into nontransforming ventricular endocardial cells, followed by the addition of either TGFβ2 or BMP-2, results in EMT. TGFβR3 lacking the entire cytoplasmic domain, or only the 3 C-terminal amino acids that are required to bind GIPC, fails to support EMT in response to TGFβ2 or BMP-2. Overexpression of GIPC in AVC endocardial cells enhanced EMT while siRNA-mediated silencing of GIPC in ventricular cells overexpressing TGFβR3 significantly inhibited EMT. Targeting of specific ALK’s by siRNA revealed that TGFβR3-mediated EMT requires ALK2 and ALK3, in addition to ALK5, but not ALK4 or ALK6. Taken together, these data identify GIPC, ALK2, ALK3, and ALK5 as signaling components required for TGFβR3-mediated endothelial cell EMT.

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“…Interruption of this fine-tuning can lead to defects in cardiac development. For example, mutations in BMP receptor type I (ALK2) have been found in patients with atrial septal defects (ASDs) [43] and mice with compound heterozygosity for BMP2 and BMP4 demonstrate ventricular septal defects (VSDs), among other abnormalities [44]. Studies investigating early cardiomyocyte differentiation using P19 cells have found that BMPER expression is bimodal during differentiation [42].…”

Section: Discussionmentioning

confidence: 99%

BMPER regulates cardiomyocyte size and vessel density in vivo

Willis

Dyer

Ren

et al. 2013

Cardiovascular Pathology

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Background BMPER, an orthologue of Drosophila melanogaster Crossveinless-2, is a secreted factor that regulates bone morphogenetic protein activity in endothelial cell precursors and during early cardiomyocyte differentiation. Although previously described in the heart, the role of BMPER in cardiac development and function remain unknown. Methods BMPER-deficient hearts were phenotyped histologically and functionally using echocardiography and Doppler analysis. Since BMPER −/− mice die perinatally, adult BMPER +/− mice were challenged to pressure-overload-induced cardiac hypertrophy and hindlimb ischemia to determine changes in angiogenesis and regulation of cardiomyocyte size. Results We identify for the first time the cardiac phenotype associated with BMPER haploinsufficiency. BMPER messenger RNA and protein are present in the heart during cardiac development through at least E14.5 but is lost by E18.5. BMPER +/− ventricles are thinner and less compact than sibling wild-type hearts. In the adult, BMPER +/− hearts present with decreased anterior and posterior wall thickness, decreased cardiomyocyte size and an increase in cardiac vessel density. Despite these changes, BMPER +/− mice respond to pressure-overload-induced cardiac hypertrophy challenge largely to the same extent as wild-type mice. Conclusion BMPER appears to play a role in regulating both vessel density and cardiac development in vivo; however, BMPER haploinsufficiency does not result in marked effects on cardiac function or adaptation to pressure overload hypertrophy.

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ALK2 mutation in a patient with Down's syndrome and a congenital heart defect

Cited by 33 publications

References 24 publications

Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation

Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation

Endocardial cell epithelial-mesenchymal transformation requires Type III TGFβ receptor interaction with GIPC

BMPER regulates cardiomyocyte size and vessel density in vivo

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