BMPR2

Chr 2AD

bone morphogenetic protein receptor type 2

Also known as: BMPR-II, BMPR3, BMR2, BRK-3, POVD1, PPH1, T-ALK

NCBI Gene: 659 ENSG00000204217 OMIM: 600799

The protein is a transmembrane serine/threonine kinase receptor that binds bone morphogenetic proteins and activins to regulate SMAD transcriptional pathways involved in bone formation, embryogenesis, and adipogenesis. Mutations cause primary pulmonary hypertension (both familial and sporadic forms) and pulmonary veno-occlusive disease with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, reflecting its essential role in vascular development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease. [provided by RefSeq, May 2020]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.193 OMIM phenotypes

Clinical Summary— BMPR2

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Gene-Disease Validity (ClinGen)

congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

7 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 5.88

OE 0.08 (0.04–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.06Z-score

OE missense 0.76 (0.70–0.82)

429 obs / 567.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.08 (0.04–0.19)

0≤0.351.4

Missense OE?0.76 (0.70–0.82)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 4 / 47.9Missense obs/exp: 429 / 567.2Syn Z: 1.92

This gene — mechanism propensity

0.3495th %ile

GOF

0.5955th %ile

LOF

0.76top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.19 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNIn addition, transfection of cysteine-substituted BMPR2 markedly reduced basal and BMP4-stimulated transcriptional activity of a BMP/SMAD-responsive luciferase reporter gene (3GC2wt-Lux), compared with wildtype BMPR2, suggesting a dominant-negative effect of these mutants on SMAD signaling.1

GOFHowever, all mutants studied demonstrate a gain of function involving upregulation of p38(MAPK)-dependent proproliferative pathways.1

LOFNonsense mutations in BMPR2 are amongst the most common mutations found, where the insertion of a premature termination codon causes mRNA degradation via activation of the nonsense-mediated decay pathway leading to a state of haploinsufficiency.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References