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性原因的情况下肺动脉压升高。最小的肺动脉血管内闭塞是由于细胞和基质的增殖，并伴有血栓和血管痉挛。诊断往往会被推迟，因为劳累和呼吸困难的初始症状是非特异性的。确诊需要心导管术。近年来，随着新治疗方法的发展，确诊后的平均预期寿命已超过2-3年。骨形态发生蛋白受体II型基因的杂合性胚系突变最近在一些家族性或散发性骨质疏松症患者中被发现。然而，并不是每个患有PPH的人都被证明有BMPR2突变，也不是所有带有突变的人都会因为外显性降低而患上这种疾病。这项相互竞争的更新提案的总体目标是识别导致这种毁灭性疾病的更多基因。将在PPH家庭中进行10 cM的基因组筛查，在这些家庭中，受影响的个人在非常年轻的时候就患上了这种疾病，父母中的任何一方都没有受到影响。这种青少年形式的疾病似乎是以常染色体隐性遗传的方式遗传的。将进行连锁和关联测试，以定位幼年PPH基因。一旦绘制出来，将对该区域的候选基因进行测试，以确定任何可能导致疾病的变异。更典型的成人发病形式的第二个基因已被映射到BMPR2近端15厘米的区域。PPH2区域的位置和功能候选将在患者中进行鉴定和测序，以努力确定家族性PPH的第二个基因。最后，由于并不是每个携带BMPR2突变的人都会患上PPH，其他遗传因素或修饰基因很可能在疾病的病因学中也很重要。候选基因方法和连锁方法都将被用来确定PPH的修饰因子。将在对压力回波测试反应异常的家系中进行连锁分析。根据超声心动图的测量，15%-20%的普通人群在运动后出现肺动脉压升高。该异常反应基因可能是BMPR2突变个体PPH表型的修饰性基因。识别更多与PPH病因有关的基因不仅可以在家庭中进行更好的DNA诊断，还可以根据某人可能携带的PPH基因组合来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.