Cardiac myxomas are the most common form of primary cardiac tumor. They are benign neoplasms that cause morbidity and mortality through embolism, heart failure, and constitutional symptoms. Approximately 7% of individuals with cardiac myxomas have a familial syndrome, Carney complex, an autosomal dominant disorder in which cardiac myxomas occur in the setting of spotty pigmentation of the skin and endocrinopathy. Such cardiac myxomas can occur in all cardiac chambers, may be multicentric, and often recur. We identified a major disease locus for on human chromosome 17q24 and showed that mutations of the PRKAR1 a (R1 a subunit of protein kinase A) gene there cause Carney complex in nearly 2/3 of patients. Most PRKARla mutations result in haploinsufficiency. PRKARla-dependent tumorigenesis in Carney complex appears to require additional somatic mutation. Although loss of PRKARla heterozygosity does occasionally occur, other as yet unidentified(s) genes must play a role in the pathogenesis of Carney complex and cardiac myxomas. Delineation of mechanisms of cardiac tumorigenesis in Carney complex requires the identification of such genes and characterization of experimental models in which to study them. We have now identified a novel locus (""""""""CAR2"""""""") with odds of 24,500:1 that contains a second Carney complex disease gene. In addition, we have showed that prkarla haploinsufficient mice exhibit atrial myocyte karyomegaly, and visceral stromal tumors. Therefore, we propose [1] To identify the CAR2 gene that causes Carney complex and cardiac myxomas, [2] To characterize genes that interact with murine prkarl a to cause tumorigenesis, and [3] To assess the contribution of somatic mutation of Carney complex genes to nonfamilial, isolated human cardiac myxomas. We will use a positional cloning-candidate strategy to identify mutations in the CAR2 Carney complex disease gene. We will investigate the effects on murine prkarla dependent tumorigenesis of varied genetic backgrounds and altered gene dosage of other tumor suppressor genes. These studies will establish molecular genetic pathways that lead to tumorigenesis of the heart and other organs in Carney complex and will suggest candidate genes for the pathogenesis of common, nonfamilial cardiac myxomas. Findings will highlight potential targets for treatment of cardiac myxomas for modification of cardiac remodeling in common cardiovascular disorders such as heart failure and ischemic heart disease.
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