1. Prkar1a haploinsufficiency ameliorates the growth hormone excess phenotype in Aip-deficient mice.
- Author
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Schernthaner-Reiter MH, Trivellin G, Roetzer T, Hainfellner JA, Starost MF, and Stratakis CA
- Subjects
- Acromegaly pathology, Animals, Cyclic AMP genetics, Cyclic AMP metabolism, Disease Models, Animal, Growth Hormone genetics, Growth Hormone-Secreting Pituitary Adenoma pathology, Haploinsufficiency genetics, Humans, Mice, Phenotype, Acromegaly genetics, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit genetics, Growth Hormone-Secreting Pituitary Adenoma genetics, Intracellular Signaling Peptides and Proteins genetics
- Abstract
Mutations of the regulatory subunit (PRKAR1A) of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), leading to activation of the PKA pathway, are the genetic cause of Carney complex which is frequently accompanied by somatotroph tumors. Aryl hydrocarbon receptor-interacting protein (AIP) mutations lead to somatotroph tumorigenesis in mice and humans. The mechanisms of AIP-dependent pituitary tumorigenesis are still under investigation and evidence points to a connection between the AIP and PKA pathways. In this study, we explore the combined effects of Aip and Prkar1a deficiency on mouse phenotype and, specifically, pituitary histopathology. Aip+/- mice were compared with double heterozygous Aip+/-, Prkar1a+/- mice. The phenotype (including histopathology and serological studies) was recorded at 3, 6, 9 and 12 months of age. Detailed pituitary histological and immunohistochemical studies were performed at 12 months. Twelve-month old Aip+/- mice demonstrated phenotypic and biochemical evidence of GH excess including significantly elevated insulin-like growth factor 1 levels, larger weight and body length, higher hemoglobin and cholesterol levels and a higher frequency of growth plate thickening in comparison to Aip+/, Prkar1a+/- mice. Pituitary histopathology did not uncover any pituitary adenomas or somatotroph hyperplasia in either group. These results demonstrate a slow progression from elevated GH release to the formation of overt somatotropinomas in Aip+/- mice; the acromegalic phenotype of these mice is surprisingly ameliorated in Aip+/-, Prkar1a+/- mice. This highlights the complexities of interaction between the AIP and PKA pathway. Specifically targeting GH secretion rather than somatotroph proliferation may be an advantage in the medical treatment of AIP-dependent human acromegaly., (Published by Oxford University Press 2020.)
- Published
- 2020
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