Double outlet right ventricle: aetiologies and associations

Obler, Dita; Juraszek, Amy L.; Smoot, Leslie; Natowicz, Marvin R.

doi:10.1136/jmg.2008.057984

Cited by 104 publications

(83 citation statements)

References 187 publications

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“…Apoptosis can play a crucial role in the alignment of the arteries (20). Of note, although increased apoptosis was noted in the myocardium or the mesenchyme in the Mox2-Cre DKOs, this did not occur in the Tie2-Cre model at e13.5.…”

Section: Discussionmentioning

confidence: 98%

“…Finally, the DKOs exhibited DORV, in which both great arteries (the pulmonary artery and the aorta) originate from the right ventricle. DORV is a clinically important congenital heart defect resulting from various cellular events, including proliferation and migration defects of neural crest cells, delayed or increased apoptosis in the myocardium of the conotruncal area, and faulty left/right signaling (20). We have been able to narrow down the defective cell types that likely underlie the DKO DORV phenotype to the endothelial cells and/or the mesenchymal cells of the pulmonary and aortic valves/atrioventricular canal, where the Tie2-Cre is known to be expressed (17,18).…”

Section: Discussionmentioning

confidence: 99%

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Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects

Berman

West

Danielian

et al. 2009

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

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The retinoblastoma tumor-suppressor protein, pRb, is a member of the pocket protein family that includes p107 and p130. These proteins have well-defined roles in regulating entry into and exit from the cell cycle and also have cell cycle-independent roles in facilitating differentiation. Here we investigate the overlap between pocket protein's function during embryonic development by using conditional mutant alleles to generate Rb;p107 doublemutant embryos (DKOs) that develop in the absence of placental defects. These DKOs die between e13.5 and e14.5, much earlier than either the conditional Rb or the germline p107 single mutants, which survive to birth or are largely viable, respectively. Analyses of the e13.5 DKOs shows that p107 mutation exacerbates the phenotypes resulting from pRb loss in the central nervous system and lens, but not in the peripheral nervous system. In addition, these embryos exhibit novel phenotypes, including increased proliferation of blood vessel endothelial cells, and heart defects, including double-outlet right ventricle (DORV). The DORV is caused, at least in part, by a defect in blood vessel endothelial cells and/or heart mesenchymal cells. These findings demonstrate novel, overlapping functions for pRb and p107 in numerous murine tissues.cell cycle ͉ heart ͉ p107 ͉ retinoblastoma

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects

Berman

West

Danielian

et al. 2009

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

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“…Knock-out of various genes in mice has resulted in DORV (reviewed in Ref. 50), suggesting that DORV represents a final common pathway defect during cardiac outflow tract development. These mouse models point to the involvement of at least several signaling pathways in this aspect of heart development, including the Ras/extracellular signal-regulated kinase (Erk), transforming growth factor ␤, Wnt, Notch, retinoic acid, and others (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

“…These mouse models point to the involvement of at least several signaling pathways in this aspect of heart development, including the Ras/extracellular signal-regulated kinase (Erk), transforming growth factor ␤, Wnt, Notch, retinoic acid, and others (reviewed in Ref. 50).…”

Section: Discussionmentioning

confidence: 99%

The Ubiquitin Ligase Nedd4-1 Is Required for Heart Development and Is a Suppressor of Thrombospondin-1

Fouladkou

Chen

Jiang

et al. 2010

Journal of Biological Chemistry

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Nedd4 (Nedd4-1) is a Hect domain E3 ubiquitin ligase that also contains a C2 domain and three WW domains. Despite numerous in vitro studies, its biological function in vivo is not well understood. Here we show that disruption of Nedd4-1 in mice (leaving Nedd4-2 intact) caused embryonic lethality at mid gestation, with pronounced heart defects (double-outlet right ventricle and atrioventricular cushion defects) and vasculature abnormalities. Quantitative mass spectrometry and immunoblot analyses of lysates from the wild type and knock-out mouse embryonic fibroblasts to identify Nedd4-1 in vivo targets revealed dramatically increased amounts of thrombospondin-1 (Tsp-1) in the knock-out mouse embryonic fibroblasts and embryos. Tsp-1 is an inhibitor of angiogenesis, and its elevated level was mediated primarily by enhanced transcription. Interestingly, the administration of aspirin (an inhibitor of Tsp-1) to the pregnant heterozygote mothers led to a reduction in Tsp-1 levels and a substantial rescue of the embryonic lethality. These results suggest that Nedd4-1 is a suppressor of Tsp1 and that increased levels of Tsp-1 in the Nedd4-1 knock-out mice may have contributed to the developmental defect observed in the embryos.Ubiquitination regulates stability of many cellular proteins (mainly cytosolic) by tagging them for degradation by the 26 S proteasome (1). It also controls other cellular fates such as endocytosis and vesicular sorting of transmembrane proteins (2-4). The ubiquitination reaction is carried out by the sequential activation of E1, 4 E2, and E3 enzymes (1) , and HECW2) (6, 7). The WW domains of Nedd4 proteins usually bind their substrates by recognizing a short sequence, the PY motif ((L/P)PXY) (8 -10). Nedd4-2 was shown to regulate endocytosis of the epithelial Na ϩ channel by ubiquitination (11-15), an effect impaired in Liddle syndrome patients in whom the PY motif of the epithelial Na ϩ channel (binding site for Nedd4-2) is mutated. Other ion channels are also negatively regulated by . Although Nedd4-1 is more widely expressed than Nedd4-2, less is known about its function. Nedd4-1 was reported to bind to and regulate stability or vesicular sorting of several proteins, including CNrasGEF (21); LAPTM5 (22); the viral proteins HTLV-1 Gag (23), Marburg/Ebola (24 -26), and MLV Gag (27, 28); AP-1 (27); APOBEC3G (29); Grb10 (30, 31); and c-Cbl (32). Also, the Drosophila homolog of Nedd4-1, dNedd4, was recently shown to regulate neuromuscular synaptogenesis in flies by binding to commissureless and promoting its endocytosis (33). Nedd4-1 was also shown to indirectly regulate the function of the endocytic protein Eps15 (34). The proposed role of Nedd4-1 in regulating PTEN stability and nuclear translocation (35, 36) was recently challenged (37).Despite the numerous reports published on Nedd4-1 over the past decade, its in vivo function(s) in mammals are less clear (see "Discussion"). Here we describe the knock-out of Nedd4-1 in mice. We show that these mice exhibit severe cardiac and some vascular defects...

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“…A study has shown that trisomies 13 and 18 and deletion 22q11 increase the risk of DORV (13), although our patient refused to undergo chromosomal studies. Owing to the diversity of DORV, several distinct pathogenetic mechanisms for DORV have been postulated, including impairment of neural crest derivative migration and impairment of normal cardiac situs and looping (13). An error during neural crest development can also cause cervicocephalic artery anomalies.…”

Section: A B Cmentioning

confidence: 99%

An unusual and complex congenital heart disease in a patient with a ruptured cerebral aneurysm

Chen

Chen²,

Lu³

2014

Turkish Neurosurgery

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A 38-year-old woman had complex, congenital heart anomalies, including double-outlet right ventricle with mitral atresia, severe left ventricle hypoplasia, atrial septal defect, and severe pulmonary stenosis, for which she had not received appropriate treatment. She presented to our institution with an intense sudden-onset headache that had initiated while sleeping. Brain computed tomography indicated the presence of spontaneous subarachnoid hemorrhage. Cerebral angiography revealed a left middle cerebral artery aneurysm. Two days later, she underwent a craniotomy for aneurysm clipping. According to the pathological analysis, culture, and clinical presentation, the aneurysm was not mycotic. The patient regained consciousness after a few days postoperatively.Despite the complex and rare congenital heart disease, it is especially notable that the patient survived 38 years without treatment and later had a ruptured cerebral aneurysm that was successfully managed operatively. Our literature review indicated that some congenital heart diseases such as aortic coarctation may correlate with the presence of intracranial aneurysms. Our case is novel because there are no similar cases of complex congenital heart disease combined with a ruptured intracranial aneurysm successfully resolved operatively. We believe that this case would help clinicians deal with such complicated cases of congenital heart disease combined with intracranial aneurysms. KEywoRds:Congenital heart disease, Double-outlet right ventricle, Aneurysm ÖZOtuz sekiz yaşında bir kadında mitral atrezi, şiddetli sol ventrikül hipoplazisi, atriyal septal defekt ve şiddetli pulmoner stenozla birlikte çift çıkışlı sağ ventrikül dahil konjenital kalp anomalileri vardı ve bunlar için uygun tedavi almamıştı. Kurumumuza uyurken aniden başlayan şiddetli başağrısı ile geldi. Bilgisayarlı beyin tomografisi spontan subaraknoid kanama varlığını işaret etti. Serebral anjiyografi bir sol orta serebral arter anevrizmasını ortaya koydu. İki gün sonra anevrizmayı kliplemek için kraniyotomi yapıldı. Patoloji analizi, kültür ve klinik sunuma göre anevrizma mikotik değildi. Hastanın bilinci ameliyattan birkaç gün sonra açıldı.Karmaşık ve alışılmadık konjenital kalp hastalığına rağmen hastanın tedavi almadan 38 yıl yaşaması ve daha sonra operatif olarak başarıyla tedavi edilen bir rüptüre serebral anevrizması olması özellikle ilginçtir. Literatür derlememiz aort koarktasyonu gibi bazı konjenital kalp hastalıklarının intrakraniyal anevrizma varlığıyla ilişkili olabileceğine işaret etti. Olgumuz ameliyatla başarıyla tedavi edilen rüptüre bir intrakraniyal anevrizma ile kombine benzer bir karmaşık konjenital kalp hastalığı olgusu literatürde olmadığı için ilginçtir. Bu olgunun klinisyenlerin intrakraniyal anevrizmalarla kombine olan karmaşık konjenital kalp hastalığı olguları gibi durumlarla başa çıkmasına yardımcı olacağına inanıyoruz.ANAhTAR sÖZCÜKlER: Konjenital kalp hastalığı, Çift çıkışlı sağ ventrikül, Anevrizma

show abstract

Double outlet right ventricle: aetiologies and associations

Cited by 104 publications

References 187 publications

Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects

Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects

The Ubiquitin Ligase Nedd4-1 Is Required for Heart Development and Is a Suppressor of Thrombospondin-1

An unusual and complex congenital heart disease in a patient with a ruptured cerebral aneurysm

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