CLONING OF FAMILIAL PRIMARY PULMONARY HYPERTENSION GENE

原发性肺动脉高压(PPH)的特点是 在没有继发性病因的情况下出现肺动脉压。 血管内闭塞在最小的肺动脉发生在 细胞和基质增殖，伴有血栓和血管痉挛。因为 劳累和呼吸困难的最初症状是非特异性的， 诊断往往会被推迟。确诊需要侵入性诊断 程序。确诊后的平均预期寿命为2至3年 死亡通常是由于进行性右心衰竭。该病的病因学 这种疾病目前还不清楚。尽管大多数病例似乎都是零星的， 大约6%的病例表现出常染色体显性遗传模式 外显性降低的继承。这项建议的目的是 确定导致该疾病家族性形式的基因(S)。 在使用受影响个人的DNA样本进行全基因组搜索后 在6个家系中，在染色体2q上获得了连锁的证据。这个 最高两点LOD得分为6.97，多点联动 分析得出的最大LOD得分为7.86。单倍型分析 建立了大约25厘米的最小候选间隔，并且没有 这六个家族中的任何一个与此无关的重要证据 观察染色体区域。将对更多的家庭进行基因分型 候选区域中的标记以缩小间隔并帮助识别 潜在的候选基因。最小候选者的物理地图 将构建区间，酵母人工染色体(YAC)和 细菌人工染色体(BAC)重叠群将被组装。 其他多态标记将在YAC和Bac中被识别 重叠群更精确地映射定义了最小 时间间隔。一旦包含家族PPH基因的最小间隔 已经确定，候选人的成绩单将使用这两个 可用转录图谱以及外显子捕获方法，并分析 用于组织表达模式。领先的候选基因将被评估 了解患者和正常人之间的DNA序列差异。 家族性PPH基因的鉴定将使DNA诊断成为可能 家庭，并可能潜在地允许小说的发展 既治疗家族性形式又治疗更多的 这种危及生命的疾病的常见零星形式。

Primary pulmonary hypertension (PPH) is characterized 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. Because the initial symptoms of fatigue and dyspnea on exertion are non-specific, diagnosis can often by delayed. Definitive diagnosis requires invasive procedures. The average life expectancy after diagnosis is 2 to 3 years with death usually due to progressive right heart failure. The etiology of the disease remains unknown. Although most cases appear to be sporadic, approximately 6% of cases exhibit an autosomal dominant mode of inheritance with reduced penetrance. The aim of this proposal is to identify the gene(s) responsible for the familial form of the disorder. Following a genome-wide search using DNA samples from affected individuals in six families, evidence for linkage was obtained on chromosome 2q. The maximum two-point LOD score obtained was 6.97, and multipoint linkage analysis yielded a maximum LOD score of 7.86. Haplotype analysis established a minimum candidate interval of approximately 25 cM, and no significant evidence for any of these six families being unlinked to this chromosomal region was observed. Additional families will be genotyped for markers in the candidate region to narrow the interval and help identify potential candidate genes. A physical map of the minimum candidate interval will be constructed, and yeast artificial chromosome (YAC) and bacterial artificial chromosome (BAC) contigs will be assembled. Additional polymorphic markers will be identified in the YAC and Bac contigs more precisely map the critical recombinants defining the minimum interval. Once the smallest interval containing the familial PPH gene has been determined, candidate transcripts will be identified using both available transcript maps as well as exon-trapping methods and analyzed for tissue expression patterns. Leading candidate genes will be evaluated for DNA sequence differences between affected and normal individuals. Identification of the familial PPH gene will enable DNA diagnosis in the families and could potentially allow for the development of novel therapeutics for treatment of both the familial form as well as the more common sporadic form of this life threatening disorder.