Germline<i>BMP9</i>mutation causes idiopathic pulmonary arterial hypertension

Wang, Xiaojian; Lian, Tian‐Yu; Jiang, Xin; Liu, Shao‐Fei; Li, Suqi; Jiang, Rong; Wu, Wenhui; Ye, Jue; Chen, Cheng; Du, Yao; Xu, Xi-Qi; Wu, Yan; Peng, Fuhua; Sun, Kai; Mao, Yimin; Yu, Huan; Chen, Liang; Shyy, John Y.‐J.; Zhang, Shuyang; Zhang, Xue; Jing, Zhi‐Cheng

doi:10.1183/13993003.01609-2018

Cited by 108 publications

(135 citation statements)

References 27 publications

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“…Consistent with the hypothesis that PAH-specific variants reduce ligand stability, analysis of BMP9 levels in HEK293T cells demonstrated significantly reduced secretion of mature ligands in the supernatants of cells transfected with mutant BMP9 constructs compared with cells transfected with wild-type BMP9 65 . In support P ag e | 12 of these findings, plasma levels of BMP9 were also reduced in patients with GDF2 mutations 67 .…”

Section: [H2] Functional Effect Of Novel Gene Defectsmentioning

confidence: 62%

Molecular genetic framework underlying pulmonary arterial hypertension

et al. 2019

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| Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of highthroughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications on lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention. P ag e | 2

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Section: [H2] Functional Effect Of Novel Gene Defectsmentioning

confidence: 62%

Molecular genetic framework underlying pulmonary arterial hypertension

et al. 2019

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“…For example, participant 12-207 carries variants in FBLN2 as well as ABCC8 and GGCX, and participant W000073 carries variants in PDGFD and TBX4. Similarly, we have reported other cases from these cohorts who carry more than one rare gene variant (6,7,16), and eight such cases were identified in a Chinese cohort (14). This suggests that PAH cohort studies are starting to achieve adequate statistical power to not only expand the genes associated with pulmonary hypertension but also hint at the likely oligogenic nature of the disease in some individuals which is not surprising given the modest penetrance of most PAH genes.…”

Section: While Effects Ofmentioning

confidence: 66%

“…Variants in two other genes in the transforming growth factor-beta (TGF-b) superfamily, activin A receptor type II-like 1 (ACVRL1) and endoglin (ENG) contribute to ~0.8% of PAH cases (6), especially PAH associated with hereditary hemorrhagic telangiectasia (APAH-HHT). Variants in growth differentiation factor 2 (GDF2), encoding the ligand of BMPR2/ACVRL1 (BMP9), contribute to ~1% of PAH cases in European-enriched cohorts (6,7) and are more frequent in Chinese patients (~6.7%) (14). Variants in mothers against decapentaplegic (SMAD) genes, encoding downstream mediators of BMP signaling, contribute rarely.…”

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confidence: 99%

Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH

Zhu

Swietlik

Welch

et al. 2020

Preprint

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Background -Group 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Recent highthroughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases. Methods-To identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource -Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 2,789 cases and 18,819 controls (11,101unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzed de novo variants in 124 pediatric trios.Results -Seven genes with rare deleterious variants were significantly associated (false discovery rate <0.1) with IPAH, including three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (FBLN2, fibulin 2; PDGFD, platelet-derived growth factor D). The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most of the variants occur in conserved protein domains. Variants in known PAH gene, ACVRL1, showed association with APAH. Predicted deleterious de novo variants in pediatric cases exhibited a significant burden compared to the background mutation rate (2.5x, p=7.0E-6). At least eight novel candidate genes carrying de novo variants have plausible roles in lung/heart development.Conclusions -Rare variant analysis of a large international consortium identifies two new candidate genes -FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling but have not been previously implicated in PAH. Trio analysis predicts that ~15% of pediatric IPAH may be explained by de novo variants.

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“…More importantly, these new targets also offer the promise of a next generation of tailor-made molecular therapies that are grounded not just in animal models or the cellular phenotype of patients with established PAH, but in the genetics underlying the human condition. Interestingly, a number of these newly identified genes include components of the BMPR-II signalling pathway, such as the BMPR-II ligands BMP9 and BMP10 [28][29][30], reinforcing the importance of this receptor to disease and supporting the pursuit of therapeutic approaches that aim to restore dysfunctional BMP signalling in PAH. As this work towards the next generation of PAH therapies proceeds, the question remains whether such custom therapeutics are required to truly change the clinical landscape or whether the recycling of drugs that were developed to treat other, unrelated pathologies represents the preferred path forward.…”

mentioning

confidence: 99%

“…With the rise of high-throughput DNA sequencing technology, a number of new PAH-associated genes have recently been identified to accompany the initial identification of mutations in BMPR2, the gene encoding the bone morphogenetic protein (BMP) type II receptor (BMPR-II), nearly 20 years ago [26][27][28][29][30]. These genes have served to identify novel dysregulated signalling pathways in disease and shed light on the cellular processes that govern the initiation and progression of PAH.…”

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confidence: 99%

Repurposing benzbromarone for pulmonary arterial hypertension: can channelling the past deliver the therapy of the future?

Theilmann

Ormiston

2019

Eur Respir J

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@ERSpublicationsA new study identifies increases in the calcium activated chloride channel, TMEM16A, in the pulmonary arteries of IPAH patients and proposes the repurposing of benzbromarone, a non-specific inhibitor of the channel, as a novel therapy for the disease http://bit.ly/2ITN4ulCite this article as: Theilmann AL, Ormiston ML. Repurposing benzbromarone for pulmonary arterial hypertension: can channelling the past deliver the therapy of the future?. Eur Respir J 2019; 53: 1900583 [https://doi.org/10.1183/13993003.00583-2019.One of the most well-established hallmarks of pulmonary arterial hypertension (PAH) is the unique cellular phenotype of the pulmonary arterial smooth muscle cells (PASMCs) from PAH patients. This phenotype, which is defined by hypercontractility, excessive proliferation, apoptosis resistance and aerobic glycolysis, is intimately linked with plasma membrane depolarisation and elevated concentrations of cytosolic calcium ([Ca 2+ ] cyt ) [1-3].Over the past two decades, multiple studies have identified the altered expression or regulation of a variety of cation channels that contribute to this depolarised PASMC phenotype in PAH. These changes include the increased expression of store-operated Ca 2+ channels, including the canonical transient receptor potential (TrpC) channel, TrpC6 [4], and a reduction in voltage-gated potassium channels (K v ), such as K v 1.5 [5], which enable the efflux of K + ions from the intracellular space. Together, increased Ca 2+ influx and reduced K + efflux contribute to membrane depolarisation and a further elevation of [Ca 2+ ] cyt via the opening of voltage-dependent calcium channels (figure 1). More recently, genetic screening of both heritable PAH families and idiopathic PAH (IPAH) patient cohorts enabled the identification of heterozygous loss-of-function mutations in KCNK3, the gene encoding the TASK-1 potassium channel, in both patient populations [6,7]. KCNK3 is decreased in the monocrotaline rat model of PAH and its inhibition was found to induce aberrant pulmonary vascular cell proliferation in control rats [8]. Moreover, KCNK3 silencing promotes PASMC membrane depolarisation in vitro, offering yet another mediator of the diseased cellular phenotype in PAH [9].In comparison to this thoroughly defined role for cation handling in PAH, the potential contribution of anion channels to disease has received relatively little attention. To date, this work has largely been limited to studies of the Ca 2+ activated Cl − channel, TMEM16A, which is upregulated in the PASMCs of rats exposed to either chronic hypoxia or monocrotaline and serves as a critical contributor to PASMC

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GermlineBMP9mutation causes idiopathic pulmonary arterial hypertension

Abstract: is a new culprit gene for IPAH ranking second to BMPR2. The rare deleterious mutations in BMP9, which lead to the reduction in BMP9 secretion and impairment in BMP9 function, account for 6.7% of IPAH cases.

Cited by 108 publications

References 27 publications

Molecular genetic framework underlying pulmonary arterial hypertension

Molecular genetic framework underlying pulmonary arterial hypertension

Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH

Repurposing benzbromarone for pulmonary arterial hypertension: can channelling the past deliver the therapy of the future?

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