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

Abstract

Background: Autosomal 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.

Methods: Testing 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.

Results: While 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.

Conclusion: In 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.

Figure 1

Model of the potential impact of Nonsense-Mediated Decay (NMD) on protein expression. Activation of the NMD pathway results in the degradation of susceptible mutant transcripts, leaving only the remaining wild-type allele that produces normal BMPR2 protein. The individual may be susceptible to disease because protein amount is quantitatively but not qualitatively reduced, resulting in 'haploinsufficiency'. Mutant RNA transcripts that are resistant to NMD may result in a mutant protein with abnormal function, including the disruption of activity by normal BMPR2 protein produced by the normal allele. The potential deleterious effect of this qualitatively but not quantitatively altered protein can result in 'dominant negative' effects, and even greater susceptibility to disease.

Figure 2

Study subjects. Samples from 169 consecutive subjects with PAH were tested for a BMPR2 mutation. Of these, 44 were from patients who had no family history. The remaining 125 were from patients who had a family history of PAH.

Figure 3

Age at diagnosis of PAH: comparison of noncarriers, patients carrying a truncating BMPR2 mutation, and patients carrying a missense BMPR2 mutation. Age at diagnosis is no different between noncarriers and patients carrying a truncating BMPR2 mutation. There is a significant difference in age at diagnosis between noncarriers and patients carrying a missense BMPR2 mutation (*, P = 0.002). Values represent mean age at diagnosis; error bars represent 95% confidence intervals.

Figure 4

Outcome of BMPR2 mutation carriers with HPAH: truncating versus missense mutation carriers. Survival measured as time to death or lung transplantation, compared between the two groups. Survival is shorter among carriers with a missense mutation (log rank test, P = 0.044).

Figure 5

Penetrance of PAH as a function of age. Statistically significant difference in penetrance according to genotype and age in the comparison of the missense mutation group versus the truncating mutation group (P = 0.01).