The pathogenesis of primary pulmonary hypertension (PPH) is unknown. This project is designed to identify and locate genetic risk factors for PPH. The familial form (FPPH) is inherited as an autosomal dominant disease with incomplete penetrance. Genetic anticipation has been noted in some families but trinucleotide repeats have yet to be found. The first goal is to identify and characterize the gene for FPPH, designated PPH1. We originally mapped PPHJ1 to a 27 cM region on chromosome2q31-32 in several families using microsatellite markers and linkage analyses. We have narrowed the genetic interval to 3-4 cM and plan to continue this process by completing linkage analysis of additional FPPH families, detection of shared DNA segments between families and by looking for linkage disequilibrium in sporadic children with PPH and their parents. If we are unable to narrow the minimal genetic region further by using classical genetics we will attempt to identify PPH1 using a genomic approach. This entails the construction of physical maps using BAC libraries and radiation mapping panels. The location of all 73 ESTs known to map in the region will be confirmed and SNP coding variant swill be detected by use of a novel database-searching program written in Java. SNPs in the positional candidate genes will be genotyped our collection of FPPH pedigrees and examined for evidence of linkage disequilibrium or a shred haplotype. If this is not found, we will perform mutation detection in these genes by DNA sequence analysis. If this is unsuccessful in identifying PPH1, we will sequence the BAC contig at low coverage to detect novel ORFs. These ORFs will also be sequenced for detection of the PPH1 gene mutation(s). After PPJ1 is found, we will determine whether it is involve din sporadic PPH, or in PPH with known risk factors such as anorexic drug therapy, HIV-infection, and pulmonary hypertension in individuals with anatomically large congenital pulmonary to systemic communications. The identification of the PPH1 gene will increase the diagnostic accuracy, identification of carriers of FPPH, in addition, understanding the function of the gene may lead to new avenues of therapeutic intervention.
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