Implications of Mutations of Activin Receptor-Like Kinase 1 Gene (&lt;i&gt;ALK1&lt;/i&gt;) in Addition to Bone Morphogenetic Protein Receptor II Gene (&lt;i&gt;BMPR2&lt;/i&gt;) in Children With Pulmonary Arterial Hypertension

Fujiwara, Maya; Yagi, Hisato; Matsuoka, Rumiko; Akimoto, Kaoru; Furutani, Michiko; Imamura, Shinichiro; Uehara, Ritei; Nakayama, Tomohiro; Takao, Atsuyoshi; Nakazawa, Makoto; Saji, Tsutomu

doi:10.1253/circj.72.127

Cited by 99 publications

(84 citation statements)

References 39 publications

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“…BMP9 causes a reduction in EFNA1 in association with a reduction in ALK1, indicating that the loss of the BMPR2 coreceptor ALK1 may be as important as the loss of BMPR2 in regulating EFNA1 expression. This pathway may therefore be especially relevant in patients who develop PAH related to ALK1 mutations, with or without associated hereditary hemorrhagic telangiectasia (45).…”

Section: Discussionmentioning

confidence: 99%

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

Rhodes

Cao

et al. 2015

Am J Respir Crit Care Med

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Rationale: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.Objectives: RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts.Methods: The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse.Measurements and Main Results: Fold differences in 10 genes were significant (P , 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased b-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries. Conclusions:The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.

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Section: Discussionmentioning

confidence: 99%

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

Rhodes

Cao

et al. 2015

Am J Respir Crit Care Med

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“…In addition, about 20% of patients with idiopathic PAH were reported to have mutations in BMPRII [99,100]. A recent study has implicated mutations of ALK1 in children with PAH [101]. Over-expression of a mutant form of BMPRII in SMCs of transgenic mice causes an increase in pulmonary arterial pressure and pulmonary arterial muscularization, resembling some manifestations of PAH patients [102].…”

Section: Pulmonary Arterial Hypertensionmentioning

confidence: 99%

TGF-β signaling in vascular biology and dysfunction

2008

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Transforming growth factor (TGF)-β family members are multifunctional cytokines that elicit their effects on cells, including endothelial and mural cells, via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knock-out mouse models for TGF-β family signaling pathway components have revealed their critical importance in proper yolk sac angiogenesis. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular syndromes such as hereditary hemorrhagic telangiectasia, primary pulmonary hypertension and Marfan syndrome. In this review, we present recent advances in our understanding of the role of TGF-β receptor signaling in vascular biology and disease, and discuss how this may be applied for therapy.

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“…[14] c.1049-4_1049-2delACAinsCC Delins p.? [28] c.1054G > C Missense p.Ala352Pro [35] c.1055C > A Missense p.Ala352Asp [46] c.1061T > A Missense p.Met354Lys [29] c.1061_1068delTGCACTCA Deletion p.Met354Thrfs*35 [39] c.1062_1080dup19 Duplication p.Try361Alafs*37 [40] c.1069C > T Missense p.Gln357* [48] c.1073delG Deletion p.Gly358Alafs*57 [39] c.1083C > A Missense p.Tyr361* [14] c.1102_1105delCCGA Deletion p.Pro368Glufs*46 [14] c.1107_1108delAG Deletion p.Arg369Serfs*22 [39] c.1111G > A Missense p.Gly371Ser [19] c.1112dupG Duplication p.Thr372Hisfs*20 [23] c.1115C > T Missense p.Thr372Ile [28] c.1118delA Deletion p.Lys373Serfs*42 [19] c.1120C > T Missense p.Arg374Trp [38] c.1120_1137del18 Deletion p.Arg374_Glu379del [39] c.1121G > A Missense p.Arg374Gln [23] c.1122_1125dupGTAC Duplication p.Met376Valfs*17 [31] c.1123T > C Missense p.Tyr375His [23] c.1124A > G Missense p.Tyr375Cys [52] c.1126A > G Missense p.Met376Val [31] c.1127T > G Missense p.Met376Arg [56] Continued c.1127T > A Missense p.Met376Lys [40] c.1127T > C Missense p.Met376Thr [27] c.1129G > A Missense p.Ala377Thr [27] c.1132C > T Missense p.Pro378Ser [45] c.1133C > A Missense p.Pro378His [48] c.1135G > A Missense p.Glu379Lys [31] c.1139T > G Missense p.Val380Gly [39] c.1142T > C Missense p.Leu381Pro [60] c.1144G > C Missense p.Asp382His [19] c.1153_1157dupATCCG Duplication p.Thr387Serfs*30 [45] c.1157G > A Missense p.Arg386His [48] c.1171G > T M...…”

Section: Discussionmentioning

confidence: 99%

Novel ACLV1 Mutation Identified in Late Onset Hereditary Hemorrhagic Telangiectasia

Patrick¹,

McIntyre²,

Ramidial³

et al. 2016

IJOHNS

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Implications of Mutations of Activin Receptor-Like Kinase 1 Gene (<i>ALK1</i>) in Addition to Bone Morphogenetic Protein Receptor II Gene (<i>BMPR2</i>) in Children With Pulmonary Arterial Hypertension

Cited by 99 publications

References 39 publications

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

TGF-β signaling in vascular biology and dysfunction

Novel ACLV1 Mutation Identified in Late Onset Hereditary Hemorrhagic Telangiectasia

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