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Primary pulmonary hypertension is characterized by the obstruction of the arteries that feed blood to the lungs. This, in turn, leads to increased blood pressure. Eventually, and often, it results in death, due to an inability of the lungs to aerate the blood (respiratory failure) or the huge pressure that builds up on the right side of the heart (which feeds blood to the arteries that supply the lungs), leading to heart failure. Richard Lifton, an expert in hypertension at Yale University, comments that it is "often fatal and an unusually nasty disease that commonly affects young people". Whereas it is known that the arterial obstruction is caused by a building up of the smooth muscle cells that line the arteries, the underlying cause of the disease has, until now, remained a mystery.
In a study published in September's issue of Nature Genetics (Vol 26, No. 1, September 2000), Richard Trembath (of the University of Leicester), William Nichols (of Children's Hospital Medical Center, Cincinnati) and the International Primary Pulmonary Hypertension Consortium, have discovered a genetic cause of the familial form of primary pulmonary hypertension*. It is caused by mutations in a gene (BMPR2) encoding a receptor (a transforming growth factor beta type II receptor) that sits on the surface of cells. As its name suggests, the TGF-beta type II receptors bind soluble, extracellular molecules of the TGF-beta superfamily. Binding triggers conformational changes that are shunted down the molecule and into the cell's interior, where a series of biochemical reactions occur, ultimately affecting cell behavior, including proliferation. One of the mutations is predicted to block the binding of TGF-beta to the receptor; two others are located in a region that indicates a block in the downstream biochemical reactions. Curiously, mutations of two other genes that encode components of the TGF-beta-signalling pathway have been found in people with hereditary haemorrhagic telangiectasia (HHT). In contrast with primary pulmonary hypertension, HHT is caused by the convolution and dilation of small veins (in contrast with the blockage of arteries, seen in primary pulmonary hypertension). How these two very different disorders are caused by aberrations in the same signalling pathway has yet to be elucidated. What is now clear, though, is a means of genetic diagnosis and a potential target for the therapy of people with familial (and possibly sporadic) primary pulmonary hypertension. *A similar study has been published in September's issue of The American Journal of Human Genetics. CONTACT: Dr. Richard C. Trembath
Department of Genetics
University of Leicester, UK
Temporary contact details:
The Copthorne Harbor City Auckland Hotel
Auckland, New Zealand
Telephone: +64 9377 0349
Fax: +64 9307 8159
e-mail: rtrembat@hgmp.mrc.ac.uk Dr William C. Nichols
Assistant Professor of Pediatrics
Division of Human Genetics
Children's Hospital Medical Center
Cincinnati, Ohio 45229
Telephone: 513 636-2438
Fax: 513 636-4373
e-mail: bill.nichols@chmcc.org Dr. Richard P. Lifton
Department of Genetics and Medicine
Boyer Center for Molecular Medicine, Rm 154
Yale University School of Medicine
New Haven, Connecticut 06510, USA
Telephone +1 203 737-4420
Fax: +1 203 737 1761
e-mail: richard.lifton@yale.edu (C) Nature Genetics press release.
Message posted by: Trevor M. D'Souza
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