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Pituitary-Specific Knockout of the Carney Complex Gene Prkar1a Leads to Pituitary Tumorigenesis

Department of Molecular Virology, Immunology, and Molecular Genetics (Z.Y., L.S.K.) and Division of Endocrinology, Diabetes, and Metabolism (L.S.K.), Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210; Laboratory of Mammalian Genes and Development (L.W.-S.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; National Hormone and Peptide Program (A.F.P.), Harbor-UCLA Medical Center, Torrance, California 90502; and Department of Laboratory Medicine and Pathobiology (S.A.), University of Toronto, Toronto, Ontario, Canada M5G 2C4

Address all correspondence and requests for reprints to: Lawrence S. Kirschner, 544 TMRF, 420 West 12th Avenue, Columbus, Ohio 43210. E-mail: Lawrence.Kirschner{at}osumc.edu.

Carney complex (CNC) is an inherited neoplasia syndrome characterized by spotty skin pigmentation, myxomas, endocrine tumors, and schwannomas. Among the endocrine tumors that comprise the syndrome, GH-producing pituitary tumors are seen in approximately 10% of patients, although biochemical abnormalities of the GH axis are much more common. To explore the role of loss of the CNC gene PRKAR1A on pituitary tumorigenesis, we produced a tissue-specific knockout (KO) of this gene in the mouse. For these studies, we generated a mouse line expressing the cre recombinase in pituitary cells using the rat GHRH receptor promoter. These mice were then crossed with Prkar1a conditional null animals to produce tissue-specific KOs. Although prolactinomas were observed in KO and control mice, the KO mice exhibited a significantly increased frequency of pituitary tumors compared with wild-type or conventional Prkar1a^+/– mice. Characterization of the tumors demonstrated they were composed of cells of the Pit1 lineage that stained for GH, prolactin, and TSH. At the biochemical level, levels of GH in the serum of KO animals were markedly elevated compared with controls, regardless of the presence of a frank tumor. These data indicate that complete loss of Prkar1a is sufficient to allow the formation of pituitary tumors and abnormalities of the GH axis, in close analogy to human patients with CNC.