Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension

Abstract

BackgroundAutosomal dominant inheritance of germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for pulmonary arterial hypertension (PAH). While previous studies demonstrated a difference in severity between BMPR2 mutation carriers and noncarriers, it is likely disease severity is not equal among BMPR2 mutations. We hypothesized that patients with missense BMPR2 mutations have more severe disease than those with truncating mutations.MethodsTesting for BMPR2 mutations was performed in 169 patients with PAH (125 with a family history of PAH and 44 with sporadic disease). Of the 106 patients with a detectable BMPR2 mutation, lymphocytes were available in 96 to functionally assess the nonsense-mediated decay pathway of RNA surveillance. Phenotypic characteristics were compared between BMPR2 mutation carriers and noncarriers, as well as between those carriers with a missense versus truncating mutation.ResultsWhile there was a statistically significant difference in age at diagnosis between carriers and noncarriers, subgroup analysis revealed this to be the case only for females. Among carriers, there was no difference in age at diagnosis, death, or survival according to exonic location of the BMPR2 mutation. However, patients with missense mutations had statistically significant younger ages at diagnosis and death, as well as shorter survival from diagnosis to death or lung transplantation than those with truncating mutations. Consistent with this data, the majority of missense mutations were penetrant prior to age 36 years, while the majority of truncating mutations were penetrant after age 36 years.ConclusionIn this cohort, BMPR2 mutation carriers have more severe PAH disease than noncarriers, but this is only the case for females. Among carriers, patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations. These findings suggest that treatment and prevention strategies directed specifically at BMPR2 pathway defects may need to vary according to the type of mutation.

Molecular genetics and clinical features of Chinese idiopathic and heritable pulmonary arterial hypertension patients

“…Additional clinical characteristics are of note in the group of patients studied. The first is that the mean age of patients was around 8 yrs younger than the age of patients with IPAH or HPAH in other published series [15,26], although clinical and haemodynamic criteria for inclusion in the study were similar. It is difficult to speculate on the reasons for such a difference, since both the environmental and genetic background were different in these studies, but it shows the severity of the disease occurring in the Chinese Han population, and suggests an increased pressure of geographically and population-specific factors, in conjunction with known genetic factors when BMPR2 mutations are present, or unknown in the case of IPAH.…”

“…It has been reported that the age at diagnosis is ,10 yrs earlier in PAH patients with mutations than in those without mutations in the BMPR2 gene [15], but in a smaller series of patients, AUSTIN et al [26], found that the younger age at diagnosis in mutation carriers was confined to female patients. In our series of patients, we confirmed that the mean age at diagnosis is ,6 yrs younger in mutation carriers than in noncarriers, but while the relationship was significant in females, there was only a tendency present in males.…”

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

“…Genetic mutations in the BMPR2 gene or dysregulated BMPR2 signaling are associated with the development of PVD including pulmonary veno-occlusive disease (PVOD) (89), PAH (90,91), as well as PH associated with COPD and pulmonary fibrosis (PF) (92). Thus, impaired BMPR2 signaling is a unifying feature in the pathogenesis of PVD and the development of PH.…”

Heritable pulmonary hypertension: from bench to bedside

“…In an international observational study, EVANS et al [13] demonstrated that, in patients with idiopathic, familial and anorexigen-associated PAH, the presence of a BMPR2 mutation is associated with an increased risk of death or lung transplantation. In another study, AUSTIN et al [59] demonstrated the implication of particular BMPR2 mutation types (missense, truncating, large rearrangement or splice defect) in the phenotypic expression of the disease, a result that was not confirmed in the French cohort [60]. Finally, since PAH mostly occurs in females irrespective of BMPR2 mutation status, it has been suggested that oestrogens and oestrogen metabolism might play a role in the pathogenesis of PAH [59,61].…”