Bone Morphogenetic Protein Receptor 2 Mutation Research Articles

Dysregulated Smooth Muscle Cell BMPR2-ARRB2 Axis Causes Pulmonary Hypertension.

Mutations in BMPR2 (bone morphogenetic protein receptor 2) are associated with familial and sporadic pulmonary arterial hypertension (PAH). The functional and molecular link between loss of BMPR2 in pulmonary artery smooth muscle cells (PASMC) and PAH pathogenesis warrants further investigation, as most investigations focus on BMPR2 in pulmonary artery endothelial cells. Our goal was to determine whether and how decreased BMPR2 is related to the abnormal phenotype of PASMC in PAH. SMC-specific Bmpr2-/- mice (BKOSMC) were created and compared to controls in room air, after 3 weeks of hypoxia as a second hit, and following 4 weeks of normoxic recovery. Echocardiography, right ventricular systolic pressure, and right ventricular hypertrophy were assessed as indices of pulmonary hypertension. Proliferation, contractility, gene and protein expression of PASMC from BKOSMC mice, human PASMC with BMPR2 reduced by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation were compared to controls, to investigate the phenotype and underlying mechanism. BKOSMC mice showed reduced hypoxia-induced vasoconstriction and persistent pulmonary hypertension following recovery from hypoxia, associated with sustained muscularization of distal pulmonary arteries. PASMC from mutant compared to control mice displayed reduced contractility at baseline and in response to angiotensin II, increased proliferation and apoptosis resistance. Human PASMC with reduced BMPR2 by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation showed a similar phenotype related to upregulation of pERK1/2 (phosphorylated extracellular signal related kinase 1/2)-pP38-pSMAD2/3 mediating elevation in ARRB2 (β-arrestin2), pAKT (phosphorylated protein kinase B) inactivation of GSK3-beta, CTNNB1 (β-catenin) nuclear translocation and reduction in RHOA (Ras homolog family member A) and RAC1 (Ras-related C3 botulinum toxin substrate 1). Decreasing ARRB2 in PASMC with reduced BMPR2 restored normal signaling, reversed impaired contractility and attenuated heightened proliferation and in mice with inducible loss of BMPR2 in SMC, decreasing ARRB2 prevented persistent pulmonary hypertension. Agents that neutralize the elevated ARRB2 resulting from loss of BMPR2 in PASMC could prevent or reverse the aberrant hypocontractile and hyperproliferative phenotype of these cells in PAH.

Significance of BMPR2 mutations in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a debilitating disease that results from progressive remodeling and inflammation of pulmonary arteries. PAH develops gradually, is difficult to diagnose, and has a high mortality rate. Although mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene has been identified as the main genetic cause of PAH, the underlying pathways involving the pathophysiology of PAH are complex and still not fully understood. Endothelial dysfunction has been observed in PAH development that results in a multitude of disturbances in the cellular processes in pulmonary vessels. Changes in the pulmonary vasculature caused by the disruption of BMPR2 signaling are observed in three main vascular components; endothelial cells, smooth muscle cells, and fibroblasts. BMPR2 also has a prominent role in maintenance of the immune system. The disruption of BMPR2 signaling pathway causes an increased degree of inflammation and decreases the ability of the immune system to resolve it. Inflammatory processes and changes in pulmonary vasculature interact with one another, resulting in the progression of chronic PAH. In this review, we highlight the various components of vascular remodeling and immune response that are caused by disruption of BMPR2 signaling, including the clinical evidence and the prospects of these components as a potential target for PAH therapy. Indeed, development of drugs to target the pathogenic pathways involved in PAH may complement existing treatment regimens and improve patient prognosis.

Abstract 15826: SCUBE1 Controls BMPR2-relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a morbid vascular disease where mutations of bone morphogenetic protein receptor 2 (BMPR2) control pulmonary endothelial pathophenotypes. Transcriptomic screening from endothelial cells (ECs) derived from hereditary BMPR2-driven disease offers an opportunity to identify novel effectors in PAH pathogenesis. Methods: Public RNA-sequencing data were analyzed from inducible pluripotent stem (iPS) cell-derived endothelial cells with and without BMPR2 mutations. Candidate genes were assessed in cultured pulmonary arterial ECs (PAECs) and in rodent and human PAH. Correlations were assessed of human plasma expression with clinical disease indices. Results: Signal Peptide CUB-EGF-Domain Containing Protein 1 (SCUBE1), a putative binding partner to BMPR2, was differentially expressed in ECs carrying BMPR2 mutations. SCUBE1 was enriched in PAECs, dependent on hypoxia inducible factor-1α, and downregulated by PAH triggers, including BMPR2 knockdown, hypoxia, and IL-1β exposure. In vitro analyses defined SCUBE1 as a pathogenic effector activating BMPR2-associated SMAD1/5/9, thus regulating endothelial angiogenic potential, proliferation, and apoptosis. SCUBE1 was decreased specifically in plasma and lungs in rodents and patients with PAH but not in those with pulmonary hypertension due to left heart disease, or in the patients of other acute and chronic cardiopulmonary pathologies, including pneumonia, acute lung injury, chronic obstructive pulmonary disease, ischemic heart disease, and cardiomyopathy. An optimal plasma SCUBE1 cut point of 5.02 ng/mL was defined to diagnose PAH from control cohort with a sensitivity of 0.65 and a specificity of 0.82. In PAH patients, plasma SCUBE1 levels negatively correlated with pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular dysfunction. Conclusions: Guided by iPSC-EC sequencing, SCUBE1 was identified as a downregulated secreted factor in PAH, controlling endothelial pathophenotypes and correlated with disease indices. Clinically, SCUBE1 is a sensitive and specific PAH diagnostic marker. It may also serve as a therapeutic target given its inherent links to controlling PAH predisposition and severity.

Genetics of pulmonary hypertension and high-altitude pulmonary edema.

Heritable pulmonary arterial hypertension (PAH) is an autosomal dominantly inherited disease caused by mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene and/or genes of its signaling pathway in ~85% of patients. A genetic predisposition to high-altitude pulmonary edema (HAPE) has long been suspected because of familial HAPE cases, but very few possibly disease-causing mutations have been identified to date. This minireview provides an overview of genetic analyses investigating common polymorphisms in HAPE-susceptible patients and the directed identification of disease-causing mutations in PAH patients. Increased pulmonary artery pressure is highlighted as an overlapping clinical feature of the two diseases. Moreover, studies showing increased pulmonary artery pressures in HAPE-susceptible patients during exercise or hypoxia as well as in healthy BMPR2 mutation carriers are illustrated. Finally, high-altitude pulmonary hypertension is introduced and future research perspectives outlined.

Pulmonary Artery Smooth Muscle Cell Bone Morphogenetic Protein 2 Promotes Pulmonary Endothelial Cell Migration and Angiogenesis

BACKGROUNDPulmonary Arterial Hypertension (PAH) is an incurable disease and remains a significant cause of morbidity and mortality in children and adults. In PAH, pulmonary arteries narrow in diameter which increases blood flow resistance in the lungs. Eventually the increase in pulmonary blood pressure causes irreversible damage to the heart. There are a variety of reasons why the pulmonary arteries become obstructed, known and unknown; yet, the molecular mechanisms driving this disease remain to be elucidated. Approximately 1000 new cases of PAH are diagnosed each year in the U.S. alone. The average survival rate for patients diagnosed with PAH is 7 years. Therefore, any insight into the molecular mechanisms that promote PAH progression may represent new strategies to treat patients with PAH.OBJECTIVEUp to 20% of PAH patients with no family history of PAH carry a bone morphogenetic protein receptor 2 (BMPR2) mutation, whereas in patients with a family history of PAH up to 82% carry a BMPR2 mutation. Therefore, it appears extremely likely that BMPR2 loss of function promotes the dysfunctional angio‐proliferative phenotype of PAH. In fact, it has recently been shown that in endothelial cells (EC) deficient in BMPR2 exposed to exogenous bone morphogenetic protein 2 (BMP2), a ligand for BMPR2, are migratory compared to control cells. To determine if the loss of BMPR2 promotes the PAEC dysfunctional angiogenesis observed in patients with PAH, we used cells from control and PAH patients to determine the role of pulmonary artery smooth muscle cell (PASMC) secreted BMP2 in promoting the migration of pulmonary artery endothelial cells (PAEC) and angiogenesis.METHODSPASMC and PAEC from control and PAH patients were examined for the expression of BMPR2 and BMP2. Cell migration, cell invasion, and angiogenetic assays were performed using PASMC and PAEC from control and PAH patients to assess differences in migration, invasion, and angiogenesis.RESULTSPAEC from PAH patients have a significant reduction in the expression of BMPR2, consistent with published reports. PASMC from PAH secrete BMP2, while BMP2 is undetectable in control cells. Co‐culturing PAH PASMC with PAH PAEC promotes PAEC migration. This migration is further enhanced in the presence of exogenous BMP2. PAH PASMC co‐cultured with PAH PAEC promote the development of PAEC‐derived angiogenetic masses. This dysfunctional angiogenetic response is further amplified in the presence of exogenous BMP2. In contrast, control PAEC exposed to control PASMC respond normally and do not form disorganized masses of vessels. Control PAEC exposed to exogenous BMP2 further promotes a normal angiogenetic response.CONCLUSIONSPASMC from PAH patients secrete BMP2. BMP2 exposure promotes the migration of PAH PAEC and a dysfunctional angiogenetic response. In contrast, BMP2 promotes a normal angiogenetic response when added to co‐cultures of control PASMC and PAEC. These data suggest that in PAH, angiogenesis becomes dysfunctional in part due to PAEC exposure to BMP2; therefore, inhibitors of BMP2 may represent a therapeutic strategy to pursue in the treatment of PAH.

2018 AHA Late-Breaking Basic Science Abstracts.

2018 AHA Late-Breaking Basic Science Abstracts.

PTGIS is a Novel Susceptibility Gene for Pulmonary Arterial Hypertension

Background: Genetic variants such as inactivating mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene account for approximately 15-20% of the etiology of idiopathic pulmonary arterial hypertension (IPAH). Increasing evidence indicates the existence of other IPAH susceptibility genes. Methods: The whole-genome sequencing was performed in a discovery cohort including 42 IPAH patients who are lacking BMPR2 mutations. Putative IPAH genes were validated in an independent cohort that included 188 IPAH patients and 968 healthy controls. Functional assessments were conducted to analyze the effects of candidate genetic variants on transcript splicing, enzymatic activity and function. Results: An enrichment of rare variants in the gene encoding prostacyclin synthase (PTGIS) was initially identified by the whole-genome sequencing. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In total, fourteen patients (6.1%) were heterozygous for three PTGIS rare variants, including one splice-site variant (c.521 1G>A) and two missense variants (R252Q, A447T). These rare variants conferred a 7.8-fold greater risk of IPAH (95% confidence interval (CI), 3.2 to 18.8; P=5 x 10-6). Inhaled iloprost induced more significantly decrease of pulmonary vascular resistance (P=0.001) and increase of cardiac index (P A variant resulted in aberrant mRNA transcripts. The functional studies showed that the two missense variants caused a decrease in prostacyclin production and increased cell death in pulmonary microvascular endothelial cells. Conclusions: We have identified three loss-of-function rare variants in the PTGIS gene from two independent IPAH cohorts. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation and cause deleterious effects. These results provide a novel finding that PTGIS rare variants are involved in the pathogenesis of IPAH. Funding: The work was supported by the following grants: the Beijing Natural Science Foundation (7181009, 7172180), the National Natural Science Foundation of China (81320108005), the National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002, 2016-I2M-4-003), the National Key Research and Development Program of China (2016YFC0901502), Sanming Project of Medicine in Shenzhen-Professor Zhi-Cheng Jing's Group for Precise Medicine Research in Thrombosis and Vascular Disease (SZSM201502001) , and the fund from State Key Laboratory of Cardiovascular Disease (2016-kf04, 2018ZR-02). Declaration of Interest: The authors declare no competing financial interests. Ethical Approval: The study protocol was approved by the ethics committees of Shanghai Pulmonary Hospital and FuWai Hospital. The participants, who were all of Chinese Han ancestry, provided written informed consent.

Clinical and genetic characteristics of pulmonary arterial hypertension in Lebanon

BackgroundPulmonary arterial hypertension (PAH) is a rare disease with an incidence rate of 2–6 cases per million per year. Our knowledge of the disease in the Middle East and North Africa (MENA) region is limited by the small number of clinical studies and the complete absence of genetic studies.MethodsOur aim was to shed light on the clinical and genetic characteristics of PAH in Lebanon and the region by using exome sequencing on PAH patients referred to the American University of Beirut Medical Center (AUBMC). Twenty-one idiopathic, hereditary and Congenital Heart Disease (CHD) PAH patients were prospectively recruited, their clinical data summarized, and sequencing performed.ResultsThe mean age at diagnosis was 33 years with a female preponderance of 70%. The mean pulmonary artery pressure at the time of diagnosis was 55. Genetic testing showed that 5 out of 19 idiopathic and Congenital Heart Disease PAH patients had Bone Morphogenetic Protein Receptor 2 (BMPR2) mutations at 25% prevalence, with 2 of these patients exhibiting a novel mutation. It also showed the presence of 1 BMPR2 mutation with 100% penetrance in a heritable PAH family. In the remaining cases, the lack of a complete genotype/phenotype correlation entailed a multigenic inheritance; suspected interactions involved previously associated genes T-box transcription factor 4 (TBX4), Bone Morphogenic Protein 10 (BMP10) and Growth Differentiation Factor 2 (GDF2).ConclusionsThis is the first study that looks into the genetic causes of PAH, including known and new BMPR2 mutations, in the MENA region. It is also the first study to characterize the clinical features of the disease in Lebanon.

Year in review 2016: Interstitial lung disease, pulmonary vascular disease, pulmonary function, paediatric lung disease, cystic fibrosis and sleep.

Year in review 2016: Interstitial lung disease, pulmonary vascular disease, pulmonary function, paediatric lung disease, cystic fibrosis and sleep.

BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension.

The impact of bone morphogenetic protein receptor 2 (BMPR2) gene mutations on vascular remodelling in pulmonary arterial hypertension (PAH) is unknown. We sought to identify a histological profile of BMPR2 mutation carriers.Clinical data and lung histology from 44 PAH patients were subjected to systematic analysis and morphometry.Bronchial artery hypertrophy/dilatation and bronchial angiogenesis, as well as muscular remodelling of septal veins were significantly increased in PAH lungs carrying BMPR2 mutations. We found that patients displaying increased bronchial artery remodelling and bronchial microvessel density, irrespective of the mutation status, were more likely to suffer from severe haemoptysis. History of substantial haemoptysis (>50 mL) was significantly more frequent in BMPR2 mutation carriers. 43.5% of BMPR2 mutation carriers, as opposed to 9.5% of noncarriers, displayed singular large fibrovascular lesions, which appear to be closely related to the systemic lung vasculature.Our analysis provides evidence for the involvement of the pulmonary systemic circulation in BMPR2 mutation-related PAH. We show that BMPR2 mutation carriers are more prone to haemoptysis and that haemoptysis is closely correlated to bronchial arterial remodelling and angiogenesis; in turn, pronounced changes in the systemic vasculature correlate with increased pulmonary venous remodelling, creating a distinctive profile in PAH patients harbouring a BMPR2 mutation.

BMPR2 mutation is a potential predisposing genetic risk factor for congenital heart disease associated pulmonary vascular disease

BackgroundPulmonary arterial hypertension (PAH) frequently arises in patients with congenital heart disease (CHD) and can lead to pulmonary vascular disease (PVD). The present study was initiated to distinguish the predisposing effect of bone morphogenetic protein receptor 2 (BMPR2) in CHD by comparing the different mutation features of BMPR2 between CHD patients with or without PVD. Methods and results294 CHD–PVD and 161 CHD without PVD patients were enrolled. PAH was diagnosed by heart catheterization at rest after CHD was first recognized by echocardiography. PVD was defined as a pulmonary vascular resistance (PVR) more than 3Wood units. BMPR2 gene was screened by direct sequencing. A total of 24 mutations were identified, accounting for 22 of the 294 patients with CHD–PVD (7.5%) and 2 of the 161 CHD patients without PVD (1.2%, P=0.004). Female/male CHD–PVD patient ratio was 1.6:1, while in the BMPR2 mutation carriers female patients were more dominant (4.5:1, P=0.042). A significant higher BMPR2 mutation rate (12.6%) was found in repaired CHD–PVD (P=0.010). BMPR2 mutations in CHD–PVD patients were identified in different clinical phenotypes. Missense mutation of BMPR2 is the dominant mutation type. ConclusionGenetic predisposing factor may be an important component in the process of development of PVD in CHD patients. Female, repaired patients are more likely to be detected with genetic mutations.

Mutation in BMPR2 Promoter: A 'Second Hit' for Manifestation of Pulmonary Arterial Hypertension?

BackgroundHereditary pulmonary arterial hypertension (HPAH) can be caused by autosomal dominant inherited mutations of TGF-β genes, such as the bone morphogenetic protein receptor 2 (BMPR2) and Endoglin (ENG) gene. Additional modifier genes may play a role in disease manifestation and severity. In this study we prospectively assessed two families with known BMPR2 or ENG mutations clinically and genetically and screened for a second mutation in the BMPR2 promoter region.MethodsWe investigated the BMPR2 promoter region by direct sequencing in two index-patients with invasively confirmed diagnosis of HPAH, carrying a mutation in the BMPR2 and ENG gene, respectively. Sixteen family members have been assessed clinically by non-invasive methods and genetically by direct sequencing.ResultsIn both index patients with a primary BMPR2 deletion (exon 2 and 3) and Endoglin missense variant (c.1633G>A, p.(G545S)), respectively, we detected a second mutation (c.-669G>A) in the promoter region of the BMPR2 gene. The index patients with 2 mutations/variants were clinically severely affected at early age, whereas further family members with only one mutation had no manifest HPAH.ConclusionThe finding of this study supports the hypothesis that additional mutations may lead to an early and severe manifestation of HPAH. This study shows for the first time that in the regulatory region of the BMPR2 gene the promoter may be important for disease penetrance. Further studies are needed to assess the incidence and clinical relevance of mutations of the BMPR2 promoter region in a larger patient cohort.

Identification of a New Intronic BMPR2-Mutation and Early Diagnosis of Heritable Pulmonary Arterial Hypertension in a Large Family with Mean Clinical Follow-Up of 12 Years

BackgroundMutations in the bone morphogenetic protein receptor 2 (BMPR2) gene can lead to hereditary pulmonary arterial hypertension (HPAH) and are detected in more than 80% of cases with familial aggregation of the disease. Factors determining disease penetrance are largely unknown.MethodsA mean clinical follow-up of 12 years was accomplished in 46 family members including echocardiography, stress-Dopplerechocardiography and genetic analysis of TGF-β pathway genes. Right heart catheterization and RNA-analysis was performed in members with pathological findings.ResultsManifest HPAH was diagnosed in 8 members, 4 were already deceased, two died during the follow-up, two are still alive. Normal pulmonary artery systolic pressure at rest but hypertensive response to exercise has been identified in 19 family members. Analysis of BMPR2 transcripts revealed aberrant splicing due to an insertion of an intronic Alu element adjacent to exon 6. All HPAH patients and 12 further asymptomatic family members carried this insertion. During follow-up two family members carrying hypertensive response and the Alu insertion developed manifest HPAH.ConclusionThis is the first report of an intronic BMPR2 mutation due to an Alu element insertion causing HPAH in a large family which has been confirmed on RNA-level. Only those members that carried both hypertensive response and the mutation developed manifest HPAH during follow-up. Our findings highlight the importance of including further methods such as RNA analysis into the molecular genetic diagnostic of PAH patients. They suggest that at least in some families hypertensive response may be an additional risk factor for disease manifestation and penetrance.

Echocardiography of pulmonary vascular function in asymptomatic carriers ofBMPR2mutations

To the Editors: Pulmonary arterial hypertension (PAH) is a rare, life-threatening dyspnoea–fatigue syndrome, caused by progressive increase in pulmonary vascular resistance (PVR) and eventual right ventricular failure [1]. The heritable form of PAH has been shown to be associated with mutations of the gene encoding the bone morphogenetic protein receptor-2 ( BMPR2 ). Asymptomatic carriers of BMPR2 mutations are at high risk of developing PAH [2]. Careful follow-up of these subjects might help to detect early-stage disease with a more favourable response to targeted therapies. However, there is uncertainty about the optimal screening method. A recent European multicentre study showed that relatives of patients with idiopathic PAH (IPAH) present with an increased prevalence of abnormally high pulmonary artery pressure (PAP) during exercise or during low-oxygen breathing [3]. In that study, measurements of pulmonary vascular function were limited to a systolic PAP (sPAP) estimated from the maximum tricuspid regurgitation velocity (TRV) assessed by Doppler echocardiography. Here, we report on additional measurements performed in one of the participating centres, providing insight into abnormal pulmonary vascular distensibility and hypoxia-induced PVR in healthy BMPR2 carriers. This study was part of a larger multicentre European project, which included 291 relatives of 109 IPAH patients and 191 age-matched controls [3]. The participating PAH centre in Brussels, Belgium, contributed with 35 relatives of 10 index patients with IPAH and 38 healthy controls. The 35 relatives were aged mean±sd 35±14 yrs. The 38 controls were aged mean±sd 36±10 yrs, and matched for sex and body surface area. Five of the asymptomatic relatives and two of the index IPAH patients were carriers …

Understanding the Low Penetrance of Bone Morphogenetic Protein Receptor 2 Gene Mutations

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary circulation in which thrombosis, inflammation, and unbridled cellular proliferation obliterate the arterial lumen, causing progressive right heart failure and death. The pathogenesis remains enigmatic, and current therapeutic strategies are limited. In 1951, Dresdale1 published the first report of a family in which 3 first-degree relatives had what was then called primary pulmonary hypertension. Subsequently, the initial, prospective National Institutes of Health (NIH)-sponsored North American primary pulmonary hypertension registry included 11 patients who had a relevant family history (6%).2 Several features of the gene transmission were apparent by the 1980s: vertical transmission indicated a single dominant gene, transmission to offspring of either sex argued against X- or Y-linkage, and multiple skip generations highlighted an incomplete penetrance.3 Article see p 1907 The race to identify the causative gene was ultimately won simultaneously by 2 groups working in parallel. Nichols et al4 used a microsatellite marker strategy to identify the locus within families on chromosome 2q32. Then groups at Columbia Presbyterian in New York5 and an International Consortium, including Vanderbilt,6 simultaneously identified mutations in a receptor for the transforming growth factor β family, the bone morphogenetic protein receptor 2 (BMPR-2), as the cause of most cases of what is now classified as heritable pulmonary arterial hypertension (HPAH). BMPR-2 mutations have subsequently been found in between 5% and 25% of patients who have idiopathic PAH without any relevant family history.7 Mutations in other transforming growth factor beta family proteins, activin-like kinase-1 and endoglin, are unusual causes for HPAH.8 Although numerous BMPR-2 mutations have been found, in most cases (≈70%) the mutation leads to a haploinsufficient state in which cellular BMPR-2 levels are reduced by ≈50%,9 usually because the mutated transcript is subject to nonsense-mediated …

Bone morphogenetic protein receptor 2 in patients with idiopathic portal hypertension

In idiopathic portal hypertension (IPH) typical vascular lesions are present in the branches of the portal vein or in the perisinusoidal area of the liver. Similar histological alterations have been reported in the pulmonary vasculature of patients with idiopathic pulmonary artery hypertension (IPAH). As IPAH is associated with mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene, the aim of this study was to investigate whether this association might also be found in patients with IPH. Twenty-three samples belonging to 21 unrelated caucasian patients with IPH followed in the hepatic haemodynamic laboratory of the Hospital Clinic in Barcelona were included in the study. All patients were studied for the entire open reading frame and splice site of the BMPR2 gene by direct sequencing and multiple ligation probe amplification (MLPA) in order to detect large deletions/duplications. None of the 23 patients had pulmonary artery hypertension. Four patients presented one single nucleotide polymorphism (SNP) in intron 5, four patients had a SNP in exon 12 and a SNP in exon 1 was found in two cases. Two patients had both intron 5 and exon 12 polymorphisms. All SNPs were previously described. Except for these three SNPs, neither mutations nor rearrangements have been identified in the BMPR2 gene in this population. We did not detect mutations or rearrangements in the coding region of the BMPR2 gene in our patients with IPH. These findings suggest that, in contrast to IPAH, mutations in BMPR2 are not involved in the pathogenesis of IPH.

Pre-implantation genetic testing for hereditary pulmonary arterial hypertension: promise and caution

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease and most PAH patients have a poor prognosis despite standard-of-care therapies. Heritable PAH (HPAH) is usually (>80%) due to germline mutations in the bone morphogenetic protein receptor 2 ( BMPR2 ) gene [1–4]. Thus, BMPR2 mutations constitute the largest known risk for developing PAH. One of the most perplexing features of HPAH is its reduced penetrance, which confounds genetic counselling. Nearly 80% of mutation carriers have no clinical symptoms, but they can produce offspring that are affected by HPAH [5]. Thus, disease development cannot be predicted in a mutation carrier and this deficiency in our knowledge about disease penetrance results in a significant physical, emotional and economic burden in HPAH families. Because 75% of subjects with HPAH have a New York Heart Association functional class rating of III or IV at the time of …

Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations

BackgroundMutations in the bone morphogenetic protein receptor 2 (BMPR2) gene can lead to idiopathic pulmonary arterial hypertension (IPAH). This study prospectively screened for BMPR2 mutations in a large cohort of PAH-patients and compared clinical features between BMPR2 mutation carriers and non-carriers.MethodsPatients have been assessed by right heart catheterization and genetic testing. In all patients a detailed family history and pedigree analysis have been obtained. We compared age at diagnosis and hemodynamic parameters between carriers and non-carriers of BMPR2 mutations. In non-carriers with familial aggregation of PAH further genes/gene regions as the BMPR2 promoter region, the ACVRL1, Endoglin, and SMAD8 genes have been analysed.ResultsOf the 231 index patients 22 revealed a confirmed familial aggregation of the disease (HPAH), 209 patients had sporadic IPAH. In 49 patients (86.3% of patients with familial aggregation and 14.3% of sporadic IPAH) mutations of the BMPR2 gene have been identified. Twelve BMPR2 mutations and 3 unclassified sequence variants have not yet been described before. Mutation carriers were significantly younger at diagnosis than non-carriers (38.53 ± 12.38 vs. 45.78 ± 11.32 years, p < 0.001) and had a more severe hemodynamic compromise. No gene defects have been detected in 3 patients with HPAH.ConclusionThis study identified in a large prospectively assessed cohort of PAH- patients new BMPR2 mutations, which have not been described before and confirmed previous findings that mutation carriers are younger at diagnosis with a more severe hemodynamic compromise. Thus, screening for BMPR2 mutations may be clinically useful.

Emerging Pathogenetic Mechanisms of Pulmonary Arterial Hypertension: Nitric Oxide and More

Emerging Pathogenetic Mechanisms of Pulmonary Arterial Hypertension: Nitric Oxide and More

A Novel BMPR2 Mutation Associated with Pulmonary Arterial Hypertension in an Octogenarian

We describe the case of an 83-year-old man with a family history of pulmonary hypertension (PH) who presented with severe pulmonary arterial hypertension (PAH) and later tested positive for a novel bone morphogenetic protein receptor 2 (BMPR2) gene mutation. To our knowledge, this may be the oldest reported patient with PAH in whom a BMPR2 mutation was initially identified.