Early onset severe pulmonary arterial hypertension with ‘two-hit’ digenic mutations in both BMPR2 and KCNA5 genes

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated mean pulmonary artery pressure (mPAp) greater than 25 mm Hg at rest in the setting of a normal or mildly elevated left heart filling pressures [ [1] Hoeper M.M. Bogaard H.J. Condliffe R. et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013; 62 ([Suppl.]): D42-D50 Crossref PubMed Scopus (1227) Google Scholar ]. Various factors such as genetic mutations, inflammation/infection, drugs/toxins, abnormal metabolism, and altered hemodynamics have been reported in the molecular pathogenesis of PAH [ [2] Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2012; 122: 4306-4313 Crossref PubMed Scopus (467) Google Scholar ]. Among them, genetic predisposition caused by heterogeneous germline mutations of the BMPR2 (bone morphogenetic protein receptor type 2, a member of the TGFβ signaling pathway) gene has been found to be accountable for 75% of heritable PAH (HPAH) and 25% idiopathic PAH (IPAH), respectively [ [3] Soubrier F. Chung W.K. Machado R. et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62: D13-D21 Crossref PubMed Scopus (229) Google Scholar ]. Other partners in the TGF-β signaling pathways, such as ACRL1 (activin receptor-like kinase type 1), ENG (endoglin), SMAD8, and SMAD4 genes, are also reported to be involved in the PAH pathogenesis [ [3] Soubrier F. Chung W.K. Machado R. et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62: D13-D21 Crossref PubMed Scopus (229) Google Scholar ]. The pore-forming subunit, Kv1.5, forms functional voltage-gated potassium (Kv) channels in human pulmonary artery smooth muscle cells (PASMC) and abnormal potassium channel Kv1.5 function encoded by KCNA5 mutations has been previously reported in patients with IPAH [ [4] Remillard C.V. Tigno D.D. Platoshyn O. et al. Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol. 2007; 292: C1837-C1853 Crossref PubMed Scopus (128) Google Scholar ]. Other genes such as CAV1, BMP9/GDF2 and KCNK3 have also been described in association with both HPAH and IPAH [ [3] Soubrier F. Chung W.K. Machado R. et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62: D13-D21 Crossref PubMed Scopus (229) Google Scholar ].