Abstract
The ubiquitous cAMP signaling pathway is essential for endocrine tissues development and function. Molecular alterations at various levels of this signaling pathway have been described in endocrine tumors. Two genetic diseases leading to multiple endocrine tumors associated with other manifestations are caused by genetic defect of key components of the cAMP signaling pathway: McCune-Albright syndrome and Carney complex.
The McCune-Albright syndrome ([MAS]; MIM 174800) is due to early post-zygotic somatic mutations of GNAS1. These are activating mutations leading to constitutive activation of the Gs protein. The main manifestations of MAS are acromegaly, café-au-lait spots, bone fibrous dysplasia, and precocious puberty. Adrenal Cushing can also be observed in a subset of patients.
Inactivating mutations of the regulatory subunit R1A of the protein kinase A (PRKAR1A) are observed in patients with Carney complex ([CNC]; MIM 160980), a multiple neoplasia syndrome causing acromegaly, thyroid nodules, and adrenal Cushing, along with spotty skin pigmentation and cardiac myxomas. Similarly, somatic activating mutations of the catalytic subunit Cα of the protein kinase A have been more recently reported in adrenal adenomas responsible for overt-Cushing syndrome.
It has been demonstrated for most of these molecular alterations that they cause an abnormal stimulation of the cAMP signaling. The two diseases and how their genetic defect dysregulate the cAMP signaling from the cell membrane to the protein kinase A are described in this text.
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Vaczlavik, A., Bertherat, J. (2020). Molecular Alterations of the cAMP Signaling Leading to Endocrine Tumors. In: Colao, A., Jaffrain-Rea, ML., Beckers, A. (eds) Polyendocrine Disorders and Endocrine Neoplastic Syndromes. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-73082-0_11-1
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