Cloning of Familial Primary Pulmonary Hypertension Gene

描述（由申请人提供）：原发性肺动脉高压（PPH）的临床特征是在无继发原因的情况下肺动脉压升高。 最小肺动脉的血管内闭塞通过细胞和基质增殖、血栓和血管痉挛发生。 由于疲劳和劳力性呼吸困难的初始症状是非特异性的，诊断常常被延迟。 确诊需要心导管插入术。 随着近年来新疗法的发展，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II型受体基因的杂合性种系突变最近已在一些家族性或散发性骨形态发生蛋白受体基因突变的个体中被发现。 然而，并不是每个患有PPH的人都被证明有BMPR 2突变，并且并不是所有具有突变的人都由于减少的BMPR 2突变而发展出这种疾病。 这个相互竞争的更新提案的总体目标是确定导致这种破坏性疾病的其他基因。 将在PPH家族中进行10 cM基因组筛查，其中受影响的个体在非常年轻的时候就患上了疾病，父母双方都没有受到影响。 这种青少年形式的疾病似乎是以常染色体隐性方式遗传的。 将进行连锁和关联测试以绘制青少年PPH基因。 一旦定位，将对该地区的候选基因进行测试，以确定任何潜在的致病变异。 第二个基因的更典型的，成人发病形式的障碍已被映射到一个区域15厘米近端BMPR 2。 在PPH 2区域的位置和功能的候选人将被确定和测序的患者在努力确定第二个基因的家族性PPH。 最后，由于不是每个BMPR 2突变的人都会发生PPH，因此可能还有其他遗传因素或修饰基因在疾病的病因学中也很重要。 候选基因的方法以及连锁的方法将被用来确定修饰PPH。将在对负荷超声心动图试验表现出异常反应的家族中进行连锁分析。 15-20%的普通人群在运动后出现肺动脉压升高，如超声心动图所测量的。 这种异常反应基因可能是BMPR 2突变个体PPH表型的修饰因子。 鉴定有助于PPH病因学的其他基因不仅可以在家庭中进行更好的DNA诊断，而且还可以根据他们可能携带的PPH基因组合预测某人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.