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.
