Primary pulmonary hypertension (PPH) is a serious disease of unknown cause in which small arteries in the lungs become obstructed. Mean survival is less than 3 years, and women develop PPH twice as commonly as men. It is familial (FPPH) in about 6% of cases. The National FPPH Registry was established in 1994 to collect and analyze family history and clinical data from PPH families to better characterize the disease phenotype as well as to identify the underlying genetic etiology. Through the collection of 72 families, FPPH has been shown to be inherited as an autosomal dominant disorder, with incomplete penetrance and genetic anticipation. Micro-satellite marker studies in six families have identified linkage to chromosome 2q31 without evidence of genetic heterogeneity. The current application will expand the Registry in order to obtain enough PPH families to localize and clone the PPH gene, and support the DNA bank for these and further studies. Other goals include prospective and biochemical mediator studies of obligate gene carriers, who do not have clinically evident PPH.
This aim will determine which mediators first become abnormal during developing PPH, and define the natural history of pre-symptomatic diseases. In addition, the Registry will broaden its scope to include sporadic PPH patients, including those who have used appetite suppressant medications, who will be screened for gene mutations. The identification of the PPH gene and its mechanism of disease will provide pivotal knowledge about PPH, but its importance may b broader because PPH is an index disease with pathologic changes identical to those seen in vessels of many common diseases such as congenital heart or connective tissue diseases. Familial PPH demonstrates many unusual transmission characteristics, including incomplete penetrance and genetic anticipation, where the disease occurs at younger ages in subsequent generations. Genetic counseling will be provided, both as a service for PPH families, but also as a model toe examine the impact on individuals and families who receive it, with special emphasis on the impact of incomplete penetrance and genetic anticipation. The only known biologic explanation of genetic anticipation is trinucleotide repeat expansion (TRE), which is currently recognized as the basis of 11 neurologic diseases. If TRE is found to be the molecular abnormality of the PPH gene, FPPH will be the first reported non-neurologic disease due to this mechanism. If another undiscovered mechanisms for genetic anticipation exists, it will have major implications for the understanding of human molecular biology. In the future we will also research for modifier genes to explain the variable expression or course of disease.
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