BMPR1B – Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by elevated pulmonary arterial pressure leading to right‐heart failure. Heritable and idiopathic forms of PAH often harbor mutations in the BMP signaling pathway, most notably in BMPR2 and related receptors. BMPR1B (bone morphogenetic protein receptor type 1B; [HGNC:1077]) encodes a type I serine–threonine kinase that mediates BMP‐induced SMAD1/5/8 phosphorylation. Given the established role of BMP signaling in vascular remodeling, BMPR1B has been evaluated as a candidate gene in PAH cohorts.

In a screening of 43 IPAH patients lacking mutations in BMPR2, ACVRL1, and SMAD8, two heterozygous missense variants in BMPR1B were each identified in two unrelated probands: c.479G>A (p.Ser160Asn) and c.1176C>G (p.Phe392Leu) ([PMID:22374147]). No familial segregation data were available, and all carriers presented with typical childhood‐onset IPAH. These four probands constitute the first reported association between BMPR1B and PAH, supporting an autosomal‐dominant inheritance model with incomplete penetrance.

Both variants are absent or extremely rare in population databases and local controls. c.479G>A (p.Ser160Asn) affects the extracellular ligand‐binding domain, whereas c.1176C>G (p.Phe392Leu) targets the kinase domain’s activation loop. The recurrence of each variant in two unrelated probands strengthens the pathogenic plausibility of these missense alleles.

Functional assays demonstrated that the p.Phe392Leu variant significantly increased SMAD8 phosphorylation and BMP‐responsive promoter activity compared to wild‐type BMPR1B. Similarly, p.Ser160Asn enhanced SMAD1/5/8 signaling and transcriptional activation in reporter assays. These gain‐of‐function effects in vitro are consistent with hyperactive BMP signaling contributing to pulmonary vascular remodeling in PAH ([PMID:22374147]).

The mechanism of pathogenicity appears to be a gain‐of‐function of BMPR1B, contrasting with loss‐of‐function BMPR1B mutations underlying skeletal dysplasias. Upregulated BMP signaling may promote aberrant proliferation and reduced apoptosis of pulmonary arterial smooth muscle cells, hallmarks of PAH pathology.

In summary, moderate clinical validity supports BMPR1B as an IPAH gene: four unrelated probands harboring recurrent missense variants with concordant gain‐of‐function data. Additional segregation studies and animal models are warranted to reach stronger classification. Key take‐home: BMPR1B should be included in genetic testing panels for IPAH to improve diagnostic yield and inform therapeutic targeting of BMP pathways.

References

• Circulation Journal • 2012 • Missense mutations of the BMPR1B (ALK6) gene in childhood idiopathic pulmonary arterial hypertension. PMID:22374147

Evidence Based Scoring (AI generated)