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More than 200 heterozygous mutations in the type 2 BMP receptor gene,  BMPR2 , have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with  BMPR2  mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express  BMPR2  mutant products. However expression of endogenous NMD negative  BMPR2  mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative  BMPR2  mutation that results in an in-frame deletion of  BMPR2 EXON2  ( BMPR2ΔEx2 ) in HPAH patient-derived lymphocytes and in pulmonary endothelial cells (PECs) from mice carrying the same in-frame deletion of  Exon 2  ( Bmpr2    ΔEx2/+   mice). The endogenous  BMPR2ΔEx2  mutant product does not reach the cell surface and is retained in the endoplasmic reticulum. Moreover, chemical chaperones 4-PBA and TUDCA partially restore cell surface expression of  Bmpr2ΔEx2  in PECs, suggesting that the mutant product is mis-folded. We also show that PECs from  Bmpr2    ΔEx2/+   mice have defects in the BMP-induced Smad1/5/8 and Id1 signaling axis, and that addition of chemical chaperones restores expression of the Smad1/5/8 target Id1. These data indicate that the endogenous NMD negative  BMPRΔEx2  mutant product is expressed but has a folding defect resulting in ER retention. Partial correction of this folding defect and restoration of defective BMP signaling using chemical chaperones suggests that protein-folding agents could be used therapeutically in patients with these NMD negative  BMPR2  mutations.

Abnormal Trafficking of Endogenously Expressed BMPR2 Mutant Allelic Products in Patients with Heritable Pulmonary Arterial Hypertension