BMPR2 – Heritable Pulmonary Arterial Hypertension

Bone morphogenetic protein receptor II ([Gene Symbol]) is the principal gene implicated in autosomal dominant heritable pulmonary arterial hypertension (HPAH) (PMID:27770446). Heterozygous BMPR2 variants are detected in approximately 70% of familial HPAH and 10–40% of idiopathic PAH cases (PMID:27770446; PMID:18503968), with an estimated lifetime penetrance of ~20% in carriers (PMID:16429395).

Segregation studies in 35 multiplex families confirmed co-segregation of BMPR2 mutations with pulmonary hypertension, identifying five truncating and two missense mutations absent in 196 control chromosomes (PMID:10903931). In a four-generation pedigree carrying the recurrent c.1472G>A (p.Arg491Gln) variant, 8 of 22 mutation carriers were diagnosed with manifest HPAH over a 12-year follow-up (PMID:30894412; PMID:24621962).

The BMPR2 variant spectrum encompasses over 200 distinct mutations, including >44 missense, >70 nonsense/frameshift, splice-site defects, gross exonic deletions/duplications, promoter and deep-intronic alterations (PMID:16429395; PMID:15775752). Founder or recurrent alleles such as c.1472G>A (p.Arg491Gln) and c.1471C>T (p.Arg491Trp) have been described in multiple independent kindreds (PMID:10903931; PMID:14985116).

In vitro and in vivo functional assays support haploinsufficiency as the pathogenic mechanism. Missense mutations in the ligand-binding and kinase domains impair receptor trafficking and abrogate Smad1/5/8 signalling (PMID:12221115; PMID:11115378). Chemical chaperones (4-PBA, TUDCA) partially restore cell-surface expression and downstream signalling of misfolded BMPR-II mutants (e.g., C118W, ΔEx2) (PMID:18647753). Mouse models with heterozygous null or extracellular-domain Bmpr2 mutations develop pulmonary hypertension under hypoxic stress, recapitulating human phenotypes (PMID:28090303).

Reduced penetrance is modulated by additional genetic factors. Altered BMPR2 exon-12 splicing regulated by SRSF2 shifts isoform ratios and correlates with disease expression (PMID:22923426). A distal FIGN locus upstream of BMPR2 modifies HPAH risk in c.1472G>A carriers (PMID:30894412). Variants in estrogen‐metabolizing CYP1B1 and BMPR2 promoter mutations further influence penetrance and age of onset (PMID:19357154; PMID:26167679).

Clinical implications of BMPR2 testing are profound. Mutation-positive patients exhibit poorer acute vasodilator response, lower cardiac index, and higher mortality compared with noncarriers (PMID:18503968). Guidelines recommend annual multimodal screening with echocardiography, RHC, and biomarker assessment in asymptomatic carriers for early detection and intervention (PMID:33380512). Genetic counselling is essential given autosomal dominant inheritance, variable expressivity, and reduced penetrance (PMID:19555857).

In summary, heterozygous BMPR2 mutations cause autosomal dominant HPAH by haploinsufficiency, supported by extensive genetic segregation and functional data. Integration of penetrance modifiers underscores the complexity of disease expression. Key take-home: BMPR2 genotyping enables early diagnosis and precision management in HPAH.

References

• The Journal of Pathology • 2017 • The role of genetics in pulmonary arterial hypertension. PMID:27770446
• Journal of Heart and Lung Transplantation • 2008 • Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. PMID:18503968
• Human Mutation • 2006 • Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. PMID:16429395
• American Journal of Human Genetics • 2000 • Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. PMID:10903931
• Journal of Medical Genetics • 2019 • Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension. PMID:30894412
• PLOS One • 2014 • Identification of a new intronic BMPR2-mutation and early diagnosis of heritable pulmonary arterial hypertension in a large family with mean clinical follow-up of 12 years. PMID:24621962
• Genetics in Medicine • 2005 • Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. PMID:15775752
• Biochemical and Biophysical Research Communications • 2004 • Bone morphogenetic protein receptor-II mutation Arg491Trp causes malignant phenotype of familial primary pulmonary hypertension. PMID:14985116
• Molecular Biology of the Cell • 2002 • Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary hypertension. PMID:12221115
• American Journal of Human Genetics • 2001 • BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. PMID:11115378
• Human Molecular Genetics • 2008 • Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue. PMID:18647753
• Pulmonary Circulation • 2016 • Genotype-phenotype effects of Bmpr2 mutations on disease severity in mouse models of pulmonary hypertension. PMID:28090303
• Circulation • 2012 • Role of BMPR2 alternative splicing in heritable pulmonary arterial hypertension penetrance. PMID:22923426
• The European Respiratory Journal • 2009 • Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. PMID:19357154
• PLOS One • 2015 • Mutation in BMPR2 Promoter: A 'Second Hit' for Manifestation of Pulmonary Arterial Hypertension? PMID:26167679
• The European Respiratory Journal • 2021 • Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation. PMID:33380512
• Journal of the American College of Cardiology • 2009 • Genetics and genomics of pulmonary arterial hypertension. PMID:19555857

Evidence Based Scoring (AI generated)