Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve

Bonachea, Elizabeth; Chang, Shin-Tsu; Zender, Gloria; LaHaye, Stephanie; Fitzgerald-Butt, Sara; McBride, Kim L.; Garg, Vidu

doi:10.1038/pr.2014.67

Cited by 76 publications

(71 citation statements)

References 32 publications

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“…Additional reports support this finding that mutations in NOTCH1 cause malformations of the right and left sided cardiac outflow tract within families [11,14,15]. The other gene linked to BAV in humans is GATA5 , where rare sequence variants in GATA5 were identified in patients with BAV by multiple groups [16,17,18]. Similar to NOTCH1 , mutations in GATA5 have reported in a spectrum of CHD, including tetralogy of Fallot [19,20,21].…”

Section: Genetics Of Bicuspid Aortic Valvementioning

confidence: 74%

Genetic basis of aortic valvular disease

Koenig

Lincoln

Garg

2017

Current Opinion in Cardiology

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Purpose of Review Aortic valve disease is relatively common and encompasses both congenital and acquired forms. Bicuspid aortic valve (BAV) is the most common type of cardiac malformation and predisposes to the development of calcific aortic valve disease (CAVD). Since the description of the link between NOTCH1 and BAV and CAVD approximately a decade ago, there have been significant advances in the genetic and molecular understanding of these diseases. Recent findings Recent work has defined the congenital cardiac phenotypes linked to mutations in NOTCH1 and in addition, novel etiologic genes for BAV have been discovered using new genetic technologies in humans. Furthermore, several mouse models of BAV have been described defining the role of endothelial Notch1 in aortic valve morphogenesis while others have implicated new genes. These murine models along with other cell-based studies have led to molecular insights in the pathogenesis of CAVD. Summary These findings provide important insights into the molecular and genetic basis of aortic valve malformations, including BAV, specifically highlighting the etiologic role of endothelial cells. In addition, numerous investigations in the mechanisms of CAVD demonstrate the importance of developmental origins and signaling pathways as well as communication between valve endothelial cells and the underlying interstitial cells in valve disease onset and progression.

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Section: Genetics Of Bicuspid Aortic Valvementioning

confidence: 74%

Genetic basis of aortic valvular disease

Koenig

Lincoln

Garg

2017

Current Opinion in Cardiology

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“…Some studies have concluded that BAV subtypes are a result of specific genetic etiologies because Gata5 −/− mice and Nos3 −/− mice display BAVs with right–noncoronary fusion 27, 35. Further research using genetic sequencing in humans has also suggested this because human BAV patients harboring rare GATA5 mutations have a higher incidence of right–left and right–noncoronary BAVs 36. Nevertheless, a study of 1849 inbred Syrian hamsters with a high probability of homozygosity found variable aortic valve morphology and suggested that environmental factors, rather than genetics, account for BAV morphology 37, 38.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Koenig

Bosse

Majumdar

et al. 2016

JAHA

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BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background.Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1 +/− ;Nos3 −/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1 +/− ;Nos3 −/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1 +/− ;Nos3 −/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1 fl/+;Tie2‐Cre +/− ;Nos3 −/− mice recapitulate the congenital cardiac phenotype of Notch1 +/− ;Nos3 −/− embryos.ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.

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“…Mutations in GATA5 have been linked to BAV in humans (76,77), and while mice with genetic deletion of Gata5 display BAV, AscAA was not reported (78). Furthermore, it would be interesting to determine if genes that are associated with AscAA, such as FBN1 (3-6) and TGFBR1/2 (7), have a role in aortic development that predisposes to the development of AscAA.…”

Section: Ascaa In Fbn1mentioning

confidence: 99%