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Genetic basis of pulmonary arterial hypertension

Current understanding and future directions

John H. Newman, MD^*,*, Richard C. Trembath, MD, Jane A. Morse, MD, Ekkehard Grunig, MD, James E. Loyd, MD^*, Serge Adnot, MD^||, Fabio Coccolo, MD^¶, Carlo Ventura, MD, PhD^¶, John A. Phillips, III, MD^*, James A. Knowles, PhD, Bart Janssen, PhD, Oliver Eickelberg, MD^**, Saadia Eddahibi, PhD^||, Phillipe Herve, PhD, William C. Nichols, PhD and Gregory Elliott, MD

^* Vanderbilt University School of Medicine, Nashville, Tennessee, United Kingdom
Department of Medicine and Genetics, University of Leicester, Leicester, United Kingdom
Columbia University College of Physicians and Surgeons, New York, New York, USA
Heidelberg University, Heidelberg, Germany
^|| Hopital Henri Mondor, Creteil, France
^¶ University of Bologna, Bologna, Italy
^** Giessen University School of Medicine, Giessen, Germany
University Paris Sud, Paris, France
University of Cincinatti Medical School, Cincinatti, Ohio, USA
University of Utah School of Medicine, Salt Lake City, Utah, USA

View larger version (156K): [in a new window]   Figure 1 The process leading to the discovery of mutations in bone morphogenetic protein receptor type-2 (BMPR2) as the cause of familial primary pulmonary hypertension is depicted. Collection of deoxyribonucleic acid from families with sufficient numbers of affected and unaffected members allowed linkage studies using microsatellite markers that led to identification of a chromosome interval on chromosome 2, at q31–32. Candidate genes known from the Human Genome Project (HGP) in the interval were then identified and tested by deoxyribonucleic acid sequencing. Point mutations in exons of the BMPR2 gene were found that co-segregated with affected individuals known from the family pedigrees.

View larger version (24K): [in a new window]   Figure 2 Shown from left to right are exons 1–3 in the extracellular domain, involved in dimerization with BMPR1 upon activation by bone morphogenetic protein or other transforming growth factor-beta ligand. Exon 4 spans the transmembrane, and exons 5-11 represent the kinase domain that phosphorylates SMAD proteins. The cytoplasmic tail (exons 12-13) is an unusual feature of transforming growth factor-beta receptors. Most mutations are frameshift or nonsense changes that predict truncation of the gene transcript. PPH = primary pulmonary hypertension.