Abstract
Recently, rare heterozygous mutations in
were identified in patients with pulmonary arterial hypertension (PAH).
encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.
Here we determined the functional impact of
mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.
Missense BMP9 mutant proteins were expressed
and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with
variants and in control subjects. Levels were also measured in a larger cohort of control subjects (
= 120) and patients with idiopathic PAH (
= 260).
We identified a novel rare variation at the
and
loci, including copy number variation.
, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of
mutations.
Our findings demonstrate that
mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.