The role of the aryl hydrocarbon receptor interacting protein in pituitary tumorigenesis

Abstract Germline genetic variants causing loss-of-function (LOF) of the aryl hydrocarbon receptor interacting protein gene (AIP) gene cause one-third of the cases of gigantism, one-fifth of the cases of familial isolated pituitary adenoma, and up to one-fifth of the functional pituitary neuroendocrine tumors (PitNETs) diagnosed in young patients. In addition, AIP protein deficiency in somatotropinomas is a known marker of poor response to the treatment with somatostatin analogues. With a large number of PitNET cases harboring AIP pathogenic variants now reported in the literature, it has become evident that this genetic defect leads to specific clinical phenotypes that require prompt identification and customized therapeutic approaches. AIP is a widely expressed co-chaperone protein that plays a role in a variety of signaling pathways via its numerous protein–protein interactions. The physiological function of AIP in the pituitary gland and the pathogenic mechanisms leading to AIP LOF-associated tumorigenesis are complex and still only partially known. This review summarizes the most recent evidence on the role of AIP in pituitary function and tumorigenesis, the clinical significance of AIP germline defects, and the current recommendations for genetic screening, clinical follow-up, and genetic counseling.