Cloning of Familial Primary Pulmonary Hypertension Gene

点击翻译按钮获取中文摘要

EXCEED THE SPACE PROVIDED. Primary pulmonary hypertension (PPH) is characterized clinically by elevated pulmonary artery pressures in the absence of a secondary cause. Endovascular occlusion in the smallest pulmonary arteries occurs by proliferation of cells and matrix, with thrombus and vasospasm. Diagnosis can often be delayed because the initial symptoms of fatigue and dyspnea on exertion are nonspecific. Definitive diagnosis requires cardiac catheterization. Average life expectancy after diagnosis is now more than 2 to 3 years with the development of new treatments in recent years. Heterozygous germline mutations in the gene for bone morphogenetic protein receptor type II have recently been identified in some individuals with either the familial or sporadic form of the disorder. However, not everyone with PPH has been shown to have a BMPR2 mutation, and not all of those with mutations develop the disorder due to reduced penetrance. The overall aim of this competing renewal proposal is to identify additional genes that contribute to this devastating disorder. A 10 cM genome screen will be performed in PPH families in which the affected individual developed the disease at a very young age and neither parent is affected. This juvenile form of the disorder would appear to be inherited in an autosomal recessive fashion. Both tests of linkage and association will be conducted to map the juvenile PPH gene. Once mapped, candidate genes in the region will be tested to identify any potential disease causing variants. A second gene for the more typical, adult onset form of the disorder has been mapped to a region 15 cM proximal to BMPR2. Positional and functional candidates in the PPH2 region will be identified and sequenced in patients in an effort to identify a second gene for familial PPH. Finally, as not everyone with a BMPR2 mutation develops PPH, it is likely that additional genetic factors, or modifier genes, are also important in the etiology of the disease. Both a candidate gene approach as well as a linkage approach will be utilized to identify modifiers of PPH. Linkage analysis will be performed in families exhibiting an abnormal response to a stress echo test. 15-20% of the general population develops elevated pulmonary artery pressure after exercise, as measured by echocardiogram. This abnormal response gene may be a modifier of the PPH phenotype in those individuals with BMPR2 mutations. Identification of additional genes that contribute to the etiology of PPH will not only enable better DNA diagnosis in families, but may also allow for the prediction as to whether someone is likely to develop the disease based on a combination of PPH genes they might be carrying. PERFORMANCE SITE ========================================Section End===========================================