Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates

Liu, Xu; Mei, Mei; Chen, Xiang; Lu, Yulan; Dong, Xinran; Hu, Liyuan; Hu, Xiaojing; Cheng, Guoqiang; Cao, Yun; Yang, Lin; Zhou, Wenhao

doi:10.1186/s12931-019-1148-1

Cited by 25 publications

(24 citation statements)

References 38 publications

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“…In vitro studies using cells expressing these mutant Notch3 receptors, revealed increased cell viability and proliferation suggesting that these mutations have a gain-of-function action on Notch3 signalling [80]. More recently, another group also identified a synonymous single nucleotide polymorphism (SNP) in NOTCH3 (A2146A) as significantly associated with persistant PH of the newborn in a Chinese cohort, with detection in three patients [81].…”

Section: Notch3 Signalling In Pathological Vascular Remodelling-implimentioning

confidence: 99%

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

et al. 2019

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Notch signalling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1–4) regulating diverse cellular processes have been identified. Of these, Notch3 is expressed almost exclusively in vascular smooth muscle cells (VSMCs), where it is critically involved in vascular development and differentiation. Under pathological conditions, Notch3 regulates VSMC switching between the contractile and synthetic phenotypes. Abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because of the importance of Notch3 in VSMC (de)differentiation, Notch3 has been implicated in the pathophysiology of pulmonary vascular remodelling in PAH. Here we review the current literature on the role of Notch in VSMC function with a focus on Notch3 signalling in pulmonary artery VSMCs, and discuss potential implications in pulmonary artery remodelling in PAH.

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Section: Notch3 Signalling In Pathological Vascular Remodelling-implimentioning

confidence: 99%

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

et al. 2019

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“…CPS1 and SMAD9 were identified as risk genes for persistent PH of the newborn. 6 Currently, no BMPR-2 mutation associated to DS had been reported in this setting.…”

Section: Discussionmentioning

confidence: 95%

“…Nine patients were identified as harboring genetic variants, including three with pathogenic/likely pathogenic variants in TBX4 and BMPR-2 and six with variants of unknown significance in BMPR-2 , SMAD9 , TGFB1 , KCNA5 and TRPC6 . 6 Three single nucleotide polymorphisms (SNPs) in CPS1 and one SNP in NOTCH3 were significantly associated with persistent PH of the newborn. CPS1 and SMAD9 were identified as risk genes for persistent PH of the newborn.…”

Section: Discussionmentioning

confidence: 99%

Multifactorial origin of pulmonary hypertension in a child with congenital heart disease, Down syndrome, and BMPR‐2 mutation

et al. 2021

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A late preterm infant had pulmonary hypertension (PH) caused by a variety of mechanisms leading to complex management. This child had complete atrioventricular septal defect (AVSD) associated with mild left ventricular hypoplasia and Down syndrome (DS) diagnosed prenatally. The mother had been treated by antiretroviral HIV treatment during pregnancy. Aortic coarctation was diagnosed and rapidly repaired. After surgery, he required noninvasive ventilation for persisting elevated PCO2. Pulmonary CT scan showed normal bronchial tree, lung parenchymal abnormalities with mosaic aspect and hyperlucent zones and indirect signs of lung hypoplasia with peripheral microbubbles. During follow-up, severe PH was diagnosed on echocardiography without recoarctation, significant intracardiac shunting or diastolic dysfunction. The patient died after four months unable to be weaned from noninvasive ventilation. Post mortem lung biopsy showed abnormally muscularized arterioles with intimal fibrosis and pulmonary immaturity. Gentetic screening identified a BMPR-2 mutation. This patient illustrates the multifactorial origin of PH in the neonatal period. The respective contribution of left-to-right shunt, post-capillary obstruction and abnormally elevated pulmonary vascular resistances (PVR) led to perform right heart catheterization to exclude excessive shunting and restrictive physiology of the left heart. Subjects with DS are also highly susceptible to decreased lung vascular and alveolar growth, which may increase the risk for PH and lung hypoplasia. This case highlights two issues. The first one is that right heart catheterization should be discussed in neonates with unexplained PH and the second is to extend indications of genetic testing for PH genes in neonates who have unusual course of neonatal PH, particularly in the setting of associated CHD.

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“…Sequencing of idiopathic PAH (IPAH) patients identified a number of mutations in the promoter and coding regions of KCNA5 believed to affect its transcription, trafficking, and interaction with its β subunits [17,18]. A new variant has also been found in Pulmonary Hypertension of the Newborn (PPHN) [19] Transient Receptor Potential Canonical (TRPC) channels are a subfamily of non-selective cation channels, which represent a major alternative route of Ca 2+ entry outside voltage-gated Ca 2+ channels, by functioning as both store-operated (SOC) and receptor-operated (ROC) channels [20]. Pharmacological blockade and knockout experiments found a strong correlation between TRPC6 expression, capacitative Ca 2+ entry, resting cytoplasmic [Ca 2+ ], vascular tone and proliferation of rat PASMCs [21].…”

Section: Overview Of Channelopathies In Pahmentioning

confidence: 99%

Ion channels as convergence points in the pathology of pulmonary arterial hypertension

Jouen-Tachoire

Tucker

Tammaro

2021

Biochemical Society Transactions

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Pulmonary arterial hypertension (PAH) is a fatal disease of the cardiopulmonary system that lacks curative treatments. The main pathological event in PAH is elevated vascular resistance in the pulmonary circulation, caused by abnormal vasoconstriction and vascular remodelling. Ion channels are key determinants of vascular smooth muscle tone and homeostasis, and four PAH channelopathies (KCNK3, ABCC8, KCNA5, TRPC6) have been identified so far. However, the contribution of ion channels in other forms of PAH, which account for the majority of PAH patients, has been less well characterised. Here we reason that a variety of triggers of PAH (e.g. BMPR2 mutations, hypoxia, anorectic drugs) that impact channel function may contribute to the onset of the disease. We review the molecular mechanisms by which these ‘extrinsic’ factors converge on ion channels and provoke their dysregulation to promote the development of PAH. Ion channels of the pulmonary vasculature are therefore promising therapeutic targets because of the modulation they provide to both vasomotor tone and proliferation of arterial smooth muscle cells.

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Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates

Cited by 25 publications

References 38 publications

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

Multifactorial origin of pulmonary hypertension in a child with congenital heart disease, Down syndrome, and BMPR‐2 mutation

Ion channels as convergence points in the pathology of pulmonary arterial hypertension

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