Prkar1a haploinsufficiency ameliorates the growth hormone excess phenotype in Aip-deficient mice.

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.

• Authors: Marie Helene Schernthaner-Reiter, Giampaolo Trivellin, Thomas Roetzer, Johannes A Hainfellner, Matthew F Starost, Constantine A Stratakis
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 29 Issue 17 Pg. 2951-2961 (10 10 2020) ISSN: 1460-2083 [Electronic] England
• PMID: 32821937 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Oxford University Press 2020.

Chemical References

• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
• Intracellular Signaling Peptides and Proteins
• Prkar1a protein, mouse
• aryl hydrocarbon receptor-interacting protein
• Growth Hormone
• Cyclic AMP

Topics

• Acromegaly (genetics, pathology)
• Animals
• Cyclic AMP (genetics, metabolism)
• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit (genetics)
• Disease Models, Animal
• Growth Hormone (genetics)
• Growth Hormone-Secreting Pituitary Adenoma (genetics, pathology)
• Haploinsufficiency (genetics)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Mice
• Phenotype