title: Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele.
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 levels 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<or=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, that is, the lung, is not available for unaffected mutation carriers.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. rizwan.hamid@vanderbilt.edu
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
authors.forename: Joy D
authors.initials: JD
authors.lastname: Cogan
authors.forename: Lora K
authors.initials: LK
authors.lastname: Hedges
authors.forename: Eric
authors.initials: E
authors.lastname: Austin
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
mesh_terms: D000483:Alleles; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D002461:Cell Line, Transformed; D005192:Family Health; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D019683:Penetrance; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II