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

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

Human molecular genetics (2020-08-22)
Marie Helene Schernthaner-Reiter, Giampaolo Trivellin, Thomas Roetzer, Johannes A Hainfellner, Matthew F Starost, Constantine A Stratakis, Marie Helene Schernthaner-Reiter, Giampaolo Trivellin, Thomas Roetzer, Johannes A Hainfellner, Matthew F Starost, Constantine A Stratakis
要旨

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.

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製品内容

Sigma-Aldrich
アデノシン 3′,5′-環状一リン酸 トリス塩, ≥97% (HPLC), powder
Sigma-Aldrich
抗cAMP抗体, serum, from rabbit