Cloning of Familial Primary Pulmonary Hypertension Gene

描述（由申请人提供）：原发性肺动脉高压（PPH）的临床特征是在没有继发原因的情况下肺动脉压力升高。最小肺动脉的血管内闭塞是由细胞和基质增生引起的，并伴有血栓和血管痉挛。由于劳累时的疲劳和呼吸困难的初始症状是非特异性的，诊断常常会被延迟。明确诊断需要心导管检查。随着近年来新治疗方法的发展，诊断后的平均预期寿命现在超过2至3年。骨形态发生蛋白受体II型基因的杂合种系突变最近在一些家族性或散发性疾病患者中被发现。然而，并不是每个PPH患者都有BMPR2突变，也不是所有的突变患者都因外显率降低而患上这种疾病。这个竞争性更新提案的总体目标是确定导致这种毁灭性疾病的其他基因。在PPH家族中，如果受影响的个体在很小的时候就患上了这种疾病，父母双方都没有受到影响，将进行10厘米基因组筛查。这种青少年形式的疾病似乎以常染色体隐性遗传的方式遗传。将进行连锁和关联两种测试来绘制幼崽PPH基因。一旦定位，将测试该区域的候选基因，以确定任何潜在的致病变异。第二个更典型的，成人发病形式的疾病的基因已被定位到距离BMPR2近15厘米的区域。将在患者中鉴定和测序PPH2区域的位置和功能候选基因，以确定家族性PPH的第二个基因。最后，并不是每个携带BMPR2突变的人都会患上PPH，因此很可能额外的遗传因素或修饰基因在该病的病因学中也很重要。候选基因方法和连锁方法都将用于鉴定PPH的修饰因子。连锁分析将在家庭表现出异常反应的压力回声测试进行。通过超声心动图测量，15-20%的普通人群在运动后出现肺动脉压升高。这种异常反应基因可能是BMPR2突变个体PPH表型的修饰因子。确定与PPH病因有关的其他基因不仅可以在家庭中进行更好的DNA诊断，而且还可以根据一个人可能携带的PPH基因组合来预测他是否可能患上这种疾病。

DESCRIPTION (provided by applicant): 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 the 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.