Related Experiment Video
Updated: Dec 15, 2025
Evaluation of Right Ventricular Function in Experimental Models of Pulmonary Arterial Hypertension
Published on: June 27, 2025
The features of rare pathogenic BMPR2 variants in pulmonary arterial hypertension: Comparison between patients and
Zi-Chao Lyu1, Lan Wang2, Jian-Hui Lin3
1Key Laboratory of Pulmonary Vascular Medicine, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Background:
Mutations in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2) are the most common genetic risk factors underlying pulmonary arterial hypertension (PAH). However, the features of PAH-related BMPR2 rare variants remain unclear. We propose that the discrepancy of BMPR2 rare variants landscape between patients with PAH and reference population would be important to address the genetic background of PAH-related variants.
Methods:
We genotyped BMPR2 rare variants in 670 Chinese patients with pulmonary arterial hypertension. The BMPR2 rare variants were screened in 10,508 reference people from two exome databases.
Results:
The prevalence of rare BMPR2 variants in patients with PAH was significantly higher compared to the reference population (21.5%, 144/670 vs 0.87%, 91/10508, p = 1.3 × 10-118). In patients with PAH, 49% of identified BMPR2 rare variants were loss-of-function or splicing. These BMPR2 rare variants were only observed in 1% of the reference population (p = 9.0 × 10-12). Arg491, which is absent in the reference population, represented as hot-spot site (14.6%, 21/144) in PAH patients. BMPR2 missense mutations in PAH patients were more likely distributed in extracellular ligand-binding domain (ECD, 29.7% vs 11.1%, p < 0.001). Compared with Non-PAH-related variations, PAH-related missense variants tend to alter the amino acid electric status (51.4% vs 23.3%, p < 0.001).
Conclusions:
BMPR2 variants located in extracellular ligand-binding domain or altered the amino acid electric status are more pathogenic.
Insights
Rare bone morphogenetic protein receptor type 2 (BMPR2) variants are significantly more prevalent in pulmonary arterial hypertension (PAH) patients than the general population. These variants, particularly those affecting the extracellular domain, are strongly linked to PAH.
Area of Science:
- Genetics
- Cardiovascular Research
- Rare Diseases
Background:
- Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are the leading genetic cause of pulmonary arterial hypertension (PAH).
- The specific characteristics of BMPR2 rare variants contributing to PAH remain incompletely understood.
- Investigating differences in BMPR2 rare variant landscapes between PAH patients and controls is crucial for understanding PAH's genetic basis.
Purpose of the Study:
- To investigate the landscape of BMPR2 rare variants in Chinese patients with pulmonary arterial hypertension (PAH).
- To compare the prevalence and features of BMPR2 rare variants in PAH patients versus a reference population.
- To identify specific BMPR2 variant characteristics associated with increased pathogenicity in PAH.
Main Methods:
- Genotyping of BMPR2 rare variants in 670 Chinese PAH patients.
- Screening of BMPR2 rare variants in 10,508 individuals from public exome databases.
- Comparative analysis of variant prevalence, type, location, and functional impact between patient and reference cohorts.
Main Results:
- BMPR2 rare variants were significantly more frequent in PAH patients (21.5%) than in the reference population (0.87%).
- Loss-of-function or splicing variants constituted 49% of identified BMPR2 variants in PAH patients.
- A specific hotspot mutation, Arg491, was identified in PAH patients but absent in controls. Missense mutations in PAH patients were enriched in the extracellular ligand-binding domain (ECD) and tended to alter amino acid electric status.
Conclusions:
- BMPR2 variants, especially those in the extracellular ligand-binding domain (ECD) or those altering amino acid electric status, are more pathogenic in the context of pulmonary arterial hypertension (PAH).
- The distinct prevalence and characteristics of BMPR2 variants in PAH patients highlight their critical role in disease development.
More Related Videos
10:20Right Ventricular Systolic Pressure Measurements in Combination with Harvest of Lung and Immune Tissue Samples in Mice
Published on: January 16, 2013
03:45Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Related Concept Videos
01:30Pulmonary Hypertension: Classification and Pathogenesis
There are various classifications for PH, each relating to different underlying causes and also...
01:18Treatment for Pulmonary Arterial Hypertension: Endothelin Receptor Antagonists
ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme...
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:23Mitral Stenosis II: Clinical features and Diagnostic Tests
01:21Peripheral Arterial Disease II: Clinical Manifestations and Diagnostic Evaluation