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Updated: Sep 29, 2026
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary
Ayako Nishihara1, Tetsuro Watabe, Takeshi Imamura
1Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Japan.
Abstract:
Germline mutations in the BMPR2 gene encoding bone morphogenetic protein (BMP) type II receptor (BMPR-II) have been reported in patients with primary pulmonary hypertension (PPH), but the contribution of various types of mutations found in PPH to the pathogenesis of clinical phenotypes has not been elucidated. To determine the biological activities of these mutants, we performed functional assays testing their abilities to transduce BMP signals. We found that the reported missense mutations within the extracellular and kinase domains of BMPR-II abrogated their signal-transducing abilities. BMPR-II proteins containing mutations at the conserved cysteine residues in the extracellular and kinase domains were detected in the cytoplasm, suggesting that the loss of signaling ability of certain BMPR-II mutants is due at least in part to their altered subcellular localization. In contrast, BMPR-II mutants with truncation of the cytoplasmic tail retained the ability to transduce BMP signals. The differences in biological activities among the BMPR-II mutants observed thus suggest that additional genetic and/or environmental factors may play critical roles in the pathogenesis of PPH.
Insights
Germline mutations in bone morphogenetic protein type II receptor (BMPR-II) impact its signaling. Some BMPR-II mutations cause protein mislocalization, affecting function in primary pulmonary hypertension (PPH) pathogenesis.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Research
Background:
- Germline mutations in the BMPR2 gene are linked to primary pulmonary hypertension (PPH).
- The specific contribution of different BMPR2 mutations to PPH pathogenesis remains unclear.
- Understanding BMPR-II function is crucial for PPH research.
Purpose of the Study:
- To investigate the functional consequences of various BMPR2 mutations.
- To determine how different mutations affect BMP signal transduction.
- To correlate mutation types with alterations in BMPR-II protein localization and activity.
Main Methods:
- Functional assays to measure BMP signal transduction.
- Analysis of BMPR-II protein expression and subcellular localization.
- Comparison of wild-type BMPR-II with mutants harboring missense mutations or cytoplasmic tail truncation.
Main Results:
- Missense mutations in extracellular and kinase domains abolished BMPR-II signal transduction.
- Mutations at conserved cysteine residues led to cytoplasmic mislocalization of BMPR-II.
- Truncation of the cytoplasmic tail did not abolish BMP signal transduction.
- Significant differences in biological activity were observed among BMPR-II mutants.
Conclusions:
- The functional impact of BMPR2 mutations varies depending on the mutation type and location.
- Altered subcellular localization contributes to the loss of signaling in certain BMPR-II mutants.
- Additional genetic or environmental factors likely influence PPH development in patients with BMPR2 mutations.
