Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension

Wang, Hu; Li, Wen; Zhang, Weili; Sun, Kai; Song, Xiaodong; Gao, Shuo; Zhang, Channa; Hui, Rutai; Hu, Hong Yu

doi:10.1038/ejhg.2009.3

Cited by 22 publications

(25 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This discrepancy may represent alternative start sites utilized or the detection of immature mRNA. Our transcriptional start site is supported by the work of Wang et al [40] who reported a promoter polymorphism at -669 that altered a proposed SP3 site that inhibited BMPR2 expression. This change would be found in the promoter we predict while contained in the transcribed region proposed by Aldred et al Our promoter findings do not alter the principle finding reported by Aldred et al Once the transcription start site was determined approximately 1600 base pairs 5' of the transcription start site was cloned.…”

Section: Discussionsupporting

confidence: 74%

EGR1 is essential for transcriptional regulation of BMPR2

Radhika¹,

West²,

Loyd³

et al. 2011

AJMB

View full text Add to dashboard Cite

In this study, RLM-RACE was used to identify the transcriptional start site 387 bp upstream of the translational start. Evolutionarily conserved transcription factor binding sites were identified, and a series of luciferase reporter constructs driven by BMPR2 promoter elements used to determine their functional relevance. We found the promoter area from 983 bp to 90 bp upstream of the transcriptional start gave maximal activity, greater than longer constructs, with an area between 570 bp and 290 bp upstream of the transcriptional start containing an important repressor element. To characterize this repressor, we used a combination of EMSA, mutation of the EGR1 binding site, transfection with EGR1 and NAB1 constructs, and mutation of the NAB1 binding site within the EGR1 protein. From this we conclude that EGR1 is essential to BMPR2 transcription, but that NAB1 binding to EGR1 causes it to act as a repressor.

show abstract

Section: Discussionsupporting

confidence: 74%

EGR1 is essential for transcriptional regulation of BMPR2

Radhika¹,

West²,

Loyd³

et al. 2011

AJMB

View full text Add to dashboard Cite

show abstract

“…Mutations in the BMPR2 gene are present in more than approximately 70% of FPAH and up to 40% of patients with apparently sporadic idiopathic PAH (7)(8)(9). In previous study, we identified 4 exonic mutations in the BMPR2 gene in twenty Chinese PAH patients (10). To determine the mutant frequency, and ascertain the mutation spectrum for BMPR2 gene in Chinese population of PAH patients, 76 unrelated Chinese patients with PAH including 72 idiopathic PAH cases and 4 familial PAH cases were recruited and mutation screen for BMPR2 gene was performed.…”

Section: Identities and Frequencies Of Bmpr2 Mutations In Chinese Patmentioning

confidence: 94%

Identities and frequencies of BMPR2 mutations in Chinese patients with idiopathic pulmonary arterial hypertension

Wang¹,

Kim³

et al. 2010

Clinical Genetics

View full text Add to dashboard Cite

“…2,3,[17][18][19] Mutations in 5′UTR are rarely reported. In a BMPR2 mutation study, Wang et al 20 reported a promoter mutation, G-669A, in Chinese patients with FPAH. Limsuwan et al 16 demonstrated that 9 out of 30 child patients with PH/CHD harbor GGC and AGC repeats, as well as 9-bp duplication mutations.…”

Section: Discussionmentioning

confidence: 99%

Functional Mutations in 5′UTR of the BMPR2 Gene Identified in Chinese Families with Pulmonary Arterial Hypertension

et al. 2016

View full text Add to dashboard Cite

a These authors contributed equally to this work.Abstract: Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy with significant morbidity and mortality. Bone morphogenetic protein receptor type 2 (BMPR2) has been well recognized as the principal gene responsible for heritable and sporadic PAH. Four unrelated Chinese patients with PAH and their family members, both symptomatic and asymptomatic, were genetically evaluated by sequencing all exons and the flanking regions of BMPR2. Functionality of the aberrant mutations at the 5′ untranslated region (UTR) of BMPR2 in the families with PAH was determined by site mutation, transient transfection, and promoter-reporter assays. Four individual mutations in the BMPR2 gene were identified in the 4 families, respectively: 10-GGC repeats, 13-GGC repeats, 4-AGC repeats in 5′UTR, and a novel missense mutation in exon 7 (c.961C>T; p.Arg321X). Moreover, we demonstrated that (1) these 5′UTR mutations decreased the transcription of BMPR2 and (2) the GGC repeats and AGC repeats in BMPR2 5′UTR bore functional binding sites of EGR-1 and MYF5, respectively. This is the first report demonstrating the presence of functional BMPR2 5′UTR mutations in familial patients with PAH and further indicating that EGR-1 and MYF5 are potential targets for correcting these genetic abnormalities for PAH therapy.Keywords: bone morphogenetic protein type 2, pulmonary hypertension, mutation. Pulmonary arterial hypertension (PAH) is physiologically defined by a mean pulmonary arterial pressure (PAP) of 25 mmHg or greater at rest and is characterized by pathologic pulmonary vascular remodeling, including smooth muscle hypertrophy and intimal thickening. The prevalence of PAH is about 15 per million adults.1 The average age of onset is in the third decade of life, but there is wide variation within families, and childhood onset is also common. At least 6% of PAH cases have a recognized family history, in which the disease segregates as an autosomal dominant trait with incomplete penetrance and an estimated lifetime risk of 10%-20%. 2-5 Different subtypes of PAH are recognized, including idiopathic (IPAH) and heritable (HPAH) forms, as well as secondary PAH. HPAH is diagnosed in patients with proven germline mutations in genes associated with pulmonary hypertension as well as in familial cases with or without identified germline mutations. 6 The mutation of the bone morphogenetic protein type 2 receptor (BMPR2) gene has been well studied during the past 2 decades and recognized as one of the most prevalent genetic abnormalities in HPAH and IPAH. Approximately 25% of all patients with PAH have a BMPR2 mutation.

show abstract

Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension

Cited by 22 publications

References 42 publications

EGR1 is essential for transcriptional regulation of BMPR2

EGR1 is essential for transcriptional regulation of BMPR2

Identities and frequencies of BMPR2 mutations in Chinese patients with idiopathic pulmonary arterial hypertension

Functional Mutations in 5′UTR of the BMPR2 Gene Identified in Chinese Families with Pulmonary Arterial Hypertension

Contact Info

Product

Resources

About