Background: Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by raised pulmonary artery pressures with pathological changes in small pulmonary arteries. Previous studies have shown that approximately 70% of familial PAH and 11-40% of idiopathic PAH (IPAH) cases have mutations in the bone morphogenetic protein receptor type II (BMPR2) gene. In addition, mutations of activin receptor-like kinase 1 (ALK1) gene have also been reported in PAH patients. Since both BMPR2 and ALK1 genes belonging to the transforming growth factor (TGF)-β superfamily are known to predispose to PAH, mutations in other genes of the TGF-β/BMP signaling pathways may also predispose to PAH.
Methods: We screened for mutations in ENDOGLIN, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6 and SMAD8 genes, which are involved in the TGF-β/BMP signalings, in 23 patients with IPAH who had no mutations in BMPR2 or ALK1.
Results: A nonsense mutation in SMAD8 designated c.606 C>A, p.C202X was identified in one patient. The farther of this patient was also identified to have same mutation. Functional analysis showed the truncated form of SMAD8 C202X protein was not phosphorylated by constitutively active ALK3 and ALK1. The SMAD9 mutant was also unable to interact with SMAD4. The response to BMP was analyzed using SMAD4 and/or ca-ALK3. The transcriptional activition of the SMAD8 mutant was inefficient compared with SMAD8 wild type.
Conclusion: We describe the first mutation in SMAD8 in a patient with IPAH. Our findings suggest involvement of SMAD8 in the pathogenesis of PAH.