CLONING OF FAMILIAL PRIMARY PULMONARY HYPERTENSION GENE

原发性肺动脉高压（PPH）的特征是肺动脉压升高， 肺动脉压力在没有次要原因。 最小肺动脉的血管内闭塞发生在 细胞和基质增生，伴血栓形成和血管痉挛。因为 运动时的疲劳和呼吸困难的初始症状是非特异性的， 诊断往往会延迟。连续诊断需要侵入性 程序.确诊后的平均寿命为2至3年 通常死于进行性右心衰竭的病因 这种疾病仍然未知。虽然大多数病例似乎是零星的， 大约6%的病例表现出常染色体显性模式， 遗传性降低。这项建议的目的是 确定导致家族性疾病的基因。 在使用受影响个体的DNA样本进行全基因组搜索后， 在6个家系中，在2q染色体上获得了连锁的证据。的 最大两点LOD值为6.97，多点连锁 分析得出最大LOD评分为7.86。单倍型分析 建立了大约25 cM的最小候选间隔， 这六个家庭中的任何一个与此无关的重要证据 染色体区域进行观察。将对其他家庭进行基因分型， 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人的物理地图 间隔将被构建，酵母人工染色体（YAC）和 将组装细菌人工染色体（BAC）重叠群。 将在YAC和Bac中鉴定额外的多态性标记 重叠群更精确地映射限定最小值的关键重组体 interval.一旦包含家族性PPH基因的最小间隔 候选人成绩单将使用 可用的转录图谱以及外显子捕获方法，并分析 组织表达模式。将评估主要候选基因 受影响的个体和正常个体之间的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，并可能允许发展小说 用于治疗家族性形式以及更多 这种危及生命的疾病的常见散发形式。

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.