Penetrance of pulmonary arterial hypertension is modulated by the expression of normalBMPR2allele

Abstract

Familial pulmonary arterial hypertension (FPAH) is a progressive, fatal disease caused by mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2). FPAH is inherited as an autosomal dominant trait and shows incomplete penetrance in that many with BMPR2 mutations do not develop FPAH suggesting a role for, as yet unidentified, modifier genes in disease penetrance. We hypothesized that variable level of expression of the wild type (WT) BMPR2 allele could act as a modifier and influence penetrance of FPAH. WT BMPR2 levels were determined by real-time PCR analysis in lymphoblastoid (LB) cell lines derived from normal controls and individuals with FPAH. The FPAH kindreds analyzed carried mutations that result in the activation of nonsense mediated decay (NMD) pathway, which leads to the degradation of the mutant RNA thus ensuring that only the WT BMPR2 transcripts will be detected in the real-time assay. Our data show that WT and mutant BMPR2 levels can be reproducibly measured in patient derived LB cell lines and that unaffected mutation carrier derived LB cell lines have higher levels of WT BMPR2 transcripts than FPAH patient derived LB cell lines (p≤0.005). Our findings suggest that the levels of expression of WT BMPR2 allele transcripts is important in the pathogenesis of FPAH caused by NMD + mutations. Furthermore, our study illustrates a novel application of lymphoblastoid cell lines in the study of PAH, especially important because the affected site, i.e. lung is not available for unaffected mutation carriers.

Connectivity Map Analysis of Nonsense-Mediated Decay–Positive BMPR2-Related Hereditary Pulmonary Arterial Hypertension Provides Insights into Disease Penetrance

“…Nearly 80% of mutation carriers never develop the disease, but they can produce offspring that develop HPAH (11). We used gene expression profiling and layered bioinformatics analyses, including the use of cMap, to identify the cellular pathways involved in HPAH penetrance.…”

“…We have previously shown that the expression of nonmutated wild-type BMPR2 allele transcript may be one molecular mechanism of this observed reduced penetrance; however, it is likely that there are unknown additional factors and pathways that influence disease risk (10,11). Identification of such pathways that differ between affected mutation carriers and unaffected mutation carriers represents a strategy for gaining additional molecular insights into HPAH penetrance and possible discovery of new treatment options.…”

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

“…This observation is similar to hereditary predisposition to cancer, exemplified by the two-hit hypothesis proposed by KNUDSON [28] for tumour suppressor genes, which corresponds to a germ-line loss of function for one allele and a somatic loss of the second allele. In the case of PAH, the second event might be, as well as genetic, either environmental as suggested by somatic chromosomal abnormalities found in the lungs of PAH subjects [29], or epigenetic, potentially leading to decreased expression of the normal BMPR2 allele [30]. …”

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

“…Acquired somatic chromosomal abnormalities in the BMPR2 signaling pathway have also been described (6). The low penetrance of pulmonary arterial hypertension (PAH) found in nonaffected family members with a BMPR2 mutation has been attributed to a higher level of BMPR2 expression from the normal allele (7). In addition, patients with IPAH without a BMPR2 mutation or with PAH associated with other conditions have reduced expression of BMPR2 in pulmonary arteries (8).…”