<i>Bone morphogenetic protein receptor type 2</i> mutations, clinical phenotypes and outcomes of <scp>J</scp>apanese patients with sporadic or familial pulmonary hypertension

Kabata, Hiroki; Satoh, Tsuyoshi; Kataoka, Masaharu; Tamura, Yuichi; Ono, Tomohiko; Yamamoto, Miyuki; Huqun,; Hagiwara, Koichi; Fukuda, Keiichi; Betsuyaku, Tomoko; Asano, Koichiro

doi:10.1111/resp.12117

Cited by 30 publications

(30 citation statements)

References 43 publications

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“…No differences were observed in RNA expression of BMPR2 and the TGF-β type I receptor ( Figure 4A), indicating by guest on May 9, 2018 http://circ.ahajournals.org/ that TGF-β and BMP activity are similar in cardiomyocytes in BMPR2 mutation carriers and noncarriers and that other factors may play a role in the different RV adaptation in mutation carriers and noncarriers.…”

Section: Tgf-β/bmp Signalingmentioning

confidence: 85%

“…This may have limited our statistical power to identify differences between by guest on May 9, 2018 http://circ.ahajournals.org/ mutation carriers and noncarriers. However, we were able to confirm known differences in hypertrophy, fibrosis, and cardiac metabolism, which were described previously in animal models.…”

Section: Study Limitationsmentioning

confidence: 99%

“…13,14,[26][27][28] Until now, differences in survival and disease severity were mainly explained by a more severe pulmonary vascular involvement, leading to a more severe and faster disease trajectory. However, combining the fact that RV function is the main determinant of prognosis and disease severity and that the BMPR2 gene is also expressed in the RV, it can be speculated that RV function plays a role in the differential clinical phenotypes of mutation carriers and noncarriers.…”

Section: Impaired Rv Function In Bmpr2 Mutation Carriersmentioning

confidence: 99%

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Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension

et al. 2016

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cardiac metabolism, as well, were similar between mutation carriers and noncarriers. Conclusions-Despite a similar afterload, RV function is more severely affected in mutation carriers than in noncarriers. However, these differences cannot be explained by a differential transforming growth factor β, bone morphogenetic protein receptor II signaling, or cardiac adaptation. response to rather than the amount of pressure overload determines the fate of the RV in PAH patients. Patients with PAH may have an underlying genetic predisposition, in particular, a mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene.5-11 BMPR2 mutations are an autosomal dominant cause of PAH with reduced penetrance (14% in men, 42% in women) clinically characterized by a younger age and a more severe hemodynamic compromise at presentation in comparison with patients who have idiopathic PAH. 10,[12][13][14][15] The bone morphogenetic protein (BMP) receptor II encoded by the BMPR2 gene belongs to the transforming growth factor β (TGF-β) superfamily and mutations have been shown to result in a disturbed BMP/TGF-β balance. [16][17][18] Decreased BMP receptor II activity leads to an overactivated TGF-β signaling, which stimulates vasculogenesis, intimal hyperplasia, and medial smooth muscle growth in the pulmonary vasculature. 19,20 In addition, growing evidence suggests a key role for TGF-β signaling in the response to pressure overload of the heart. 21-23Although TGF-β signaling is necessary to protect the heart against uncontrolled matrix degradation and dilatation, excessive TGF-β signaling might be detrimental because of maladapted hypertrophy and myocardial dysfunction, as previously described in left heart failure. [21][22][23] Furthermore, a recent study by Hemnes et al 24 showed that the RV hypertrophic response was disturbed in pulmonary hypertensive mice carrying a BMPR2 mutation. However, whether RV function and adaptation in PAH patients carrying a BMPR2 mutation differs from PAH patients without an identified BMPR2 mutation remains currently elusive. Therefore, the aim of this study was 2-fold: (1) to determine the effects of a BMPR2 mutation on RV function in PAH patients and (2) to compare the histological and morphological characteristics of RV tissue samples from PAH patients with and without a BMPR2 mutation. Methods Study Population Clinical StudyWe retrospectively reviewed patients with pulmonary hypertension seen at the VU University Medical Center (Amsterdam, the Netherlands) between March 1995 and October 2014. Patients were eligible for this study when the results from BMPR2 mutation analysis were available. In total, 123 PAH patients were genetically screened for the presence of a BMPR2 mutation. After the exclusion of 28 patients, 95 patients were included in this study. Twenty-eight patients were carriers of a BMPR2 mutation (mutation carriers), and no BMPR2 mutation was identified in 67 sporadic PAH patients (noncarriers). Patients with a family history of PAH with no evidence of a BMPR2 mutation ...

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Section: Tgf-β/bmp Signalingmentioning

confidence: 85%

Section: Study Limitationsmentioning

confidence: 99%

Section: Impaired Rv Function In Bmpr2 Mutation Carriersmentioning

confidence: 99%

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Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension

et al. 2016

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“…At present, lots of gene mutations were found playing pathogenic roles in both familial and sporadic diseases [26, 27], then another question is that whether A1180V would be a risk factor among sporadic DCM patients as well. In our recent studies of the distributions of candidate mutations in DCM-related genes in sporadic DCM patients conducted using high-throughput sequencing technology, we identified A1180V in 1 out of 68 patients with DCM.…”

Section: Discussionmentioning

confidence: 99%

A1180V of Cardiac Sodium Channel Gene (SCN5A): Is It a Risk Factor for Dilated Cardiomyopathy or Just a Common Variant in Han Chinese?

Cheng

Yang

et al. 2013

Disease Markers

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Our previous study of a Chinese family with dilated cardiomyopathy (DCM) suggested that A1180V of the cardiac sodium channel gene (SCN5A) was associated with the disease within this family. According to data deposited in dbSNP, however, A1180V has been found in some small samples of the Asian population. In this study, we followed up the affected pedigree and expanded the investigation of the prevalence of A1180V in 460 unrelated healthy Han Chinese. Besides, we searched and analyzed it in other database as well. During the follow-up period, 1 A1180V carrier's condition deteriorated alot, and another 4 carriers progressed to DCM or atrioventricular block (AVB). We also found that the A1180V was absent among the 460 individuals (0%, 0/460), and the carrier frequency of A1180V among Chinese was about 0.51% obtained from the 1000 genome project. In conclusion, our finding suggests that A1180V is a potential risk factor for DCM, and it is extremely rare among Healthy Han Chinese.

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“…Although identification of individuals who carry genetic variants that increase the risk of developing PAH offers an opportunity for earlier diagnosis and finding a therapeutic strategy, the majority of previous studies was only focused on the protein coding regions of the most frequently mutated gene BMPR2 with the use of conventional methods such as Sanger sequencing [6, 14]. Thus, for the patients who have no mutation in BMPR2 , i.e., around 30% of HPAH and 60–90% of IPAH, another approach, which is practical for multiple genes, is necessary.…”

Section: Introductionmentioning

confidence: 99%

A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension

et al. 2017

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BackgroundPulmonary arterial hypertension (PAH) is a severe lung disease with only few effective treatments available. Familial cases of PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease makes it difficult to identify pathogenic variants in accordance with a Mendelian pattern of inheritance.MethodsTo elucidate the complex genetic basis of PAH, we obtained whole exome- or genome-sequencing data of 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 9 index patients and 300 PAH-free controls.ResultsA burden of rare variants in BMPR2 significantly contributed to the risk of the disease (p = 6.0 × 10−8). Eight of nine families carried four previously reported single nucleotide variants and four novel insertion/deletion variants in the gene. One of the novel variants was a large 6.5 kilobase-deletion. In the remaining one family, the patient carried a pathogenic variant in a member of potassium channels, KCNK3, which was the first replicative finding of channelopathy in an Asian population.ConclusionsThe variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-017-0400-z) contains supplementary material, which is available to authorized users.

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Bone morphogenetic protein receptor type 2 mutations, clinical phenotypes and outcomes of Japanese patients with sporadic or familial pulmonary hypertension

Cited by 30 publications

References 43 publications

Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension

Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension

A1180V of Cardiac Sodium Channel Gene (SCN5A): Is It a Risk Factor for Dilated Cardiomyopathy or Just a Common Variant in Han Chinese?

A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension

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