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Specific Bone Morphogenic Protein Receptor II Mutations Found in Primary Pulmonary Hypertension Cause Different Biochemical Phenotypes In Vitro* FREE TO VIEW

Alan Q. Thomas, MD; Jennifer Carneal, MS; Cheryl Markin, BS; Kirk B. Lane, PhD; John A. Phillips, III, MD; James E. Loyd, MD; Radhika Gaddipati, MBBS
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*From the Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine and Division of Medical Genetics, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN.

Correspondence to: Kirk B. Lane, PhD, Assistant Professor, Center for Lung Research, Department of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN

Chest. 2002;121(3_suppl):83S. doi:10.1378/chest.121.3_suppl.83S
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Primary pulmonary hypertension (PPH) is a progressive and fatal disease caused by proliferative occlusion of the smallest pulmonary arteries. It can occur at any age in either gender. PPH has also been recognized as a genetic disease, transmitted in an autosomal dominant manner. Mutations in the gene encoding the bone morphogenic protein receptor II (BMPRII) have been shown to be the molecular basis of familial PPH. BMPRII is a member of the transforming growth factor-β–receptor II family. Mutations in 12 of the 13 exons of BMPRII have been recognized but all produce a similar outcome, PPH. Using stable transfection of normal mouse mammary gland epithelium cells, we show that mutations in the different functional domains of BMPRII are capable of eliciting different biochemical phenotypes. Stable cell lines expressing wild-type or mutant BMPRII constructs were assayed for luciferase expression driven from a SMAD binding element-responsive promoter. The mutations constructed were those detected in PPH kindreds. Native cells express 11 times more luciferase after stimulation with the ligand bone morphogenic protein 4. Kinase domain mutations produced twice as much luciferase as the controls at baseline and expressed four times more than the baseline levels with stimulation with bone morphogenic protein 4. The cytoplasmic tail mutation expressed similar amounts of luciferase at baseline as the wild type but increased more than six times with stimulation. These data suggest that mutations in specific BMPRII domains affect bone morphogenic protein signaling differently in the presence or absence of ligand.

Abbreviations: PPH = primary pulmonary hypertension; BMP = bone morphogenic protein; BMPRII = bone morphogenic protein receptor II




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