CONTEXT

The pathogenic effect of AIP mutations (AIPmuts) in pituitary adenomas is incompletely understood. We have identified the primary mechanism of loss of function for missense AIPmuts.

OBJECTIVE

To analyze the mechanism/speed of protein turnover of wild-type (WT) and missense AIP variants, correlating protein half-life with clinical parameters.

DESIGN

Half-life and protein-protein interaction experiments and cross-sectional analysis of AIPmut positive patients' data were performed.

SETTING

Clinical academic research institution.

PATIENTS

Data was obtained from our cohort of pituitary adenoma patients and literature-reported cases.

INTERVENTIONS

Protein turnover of endogenous AIP in two cell lines and fifteen AIP variants overexpressed in HEK293 cells was analyzed via cycloheximide chase and proteasome inhibition. GST pull-down and quantitative mass spectrometry identified proteins involved in AIP degradation; results were confirmed by co-immunoprecipitation and gene knockdown. Relevant clinical data was collected.

MAIN OUTCOME MEASURES

Half-life of WT and mutant AIP proteins and its correlation with clinical parameters.

RESULTS

Endogenous AIP half-life was similar in HEK293 and lymphoblastoid cells (43.5 and 32.7h). AIP variants were divided in stable proteins (median 77.7h [IQR 60.7-92.9]), and those with short (27h [21.6-28.7]) or very short (7.7h [5.6-10.5]) half-life; proteasomal inhibition rescued the rapid degradation of mutant proteins. The experimental half-life significantly correlated with age at diagnosis of acromegaly/gigantism (r=0.411, P=0.002). The FBXO3-containing SCF complex was identified as the E3 ubiquitin-ligase recognizing AIP.

CONCLUSIONS

AIP is a stable protein, driven to ubiquitination by the SCF complex. Enhanced proteasomal degradation is a novel pathogenic mechanism for AIPmuts, with direct implications for the phenotype.

Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations

Familial pituitary tumors are increasingly recognized. While some of these cases are related to well-known syndromic conditions such as multiple endocrine neoplasia type 1 (MEN1) or Carney complex, others belong to the familial isolated pituitary adenoma (FIPA) patient group. The discovery of heterozygous, loss-of-function germline mutations in the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) in 2006 has subsequently enabled the identification of a mutation in this gene in 20% of FIPA families and 20% of childhood-onset simplex somatotroph adenomas. The exact mechanism by which the lack of AIP leads to pituitary adenomas is not clear. AIP mutations cause a low penetrance autosomal dominant disease with often a distinct phenotype characterized by young-onset, aggressive, large GH, mixed GH and PRL or PRL-secreting adenomas. This review aims to summarize currently available clinical data on AIP mutation-positive and negative FIPA patients.

Familial isolated pituitary adenomas: an emerging clinical entity.

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.

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

Are ''in silico'' predictions reliable regarding splice-site mutations? - Studies in the aryl hydrocarbon receptor-interacting protein (AIP)

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Are ''in silico'' predictions reliable regarding splice-site mutations? - Studies in the aryl hydrocarbon receptor-interacting protein (AIP)