Endocrine Abstracts

Introduction: Mutations in the aryl hydrocarbon receptor-interaction protein (AIP) gene predisposes to growth hormone or prolactin secretin adenomas, usually, manifesting before the age of 30 years old. There are 834 variants of the AIP reported in the GnomAD database and over 100 variants have been described in patients with pituitary adenomas. While the pathogenic role of variants resulting in truncated protein is beyond doubt, determination of the clinical relevance of missense variants could be challenging. In this study, we aimed to functionally assess the AIP variants identified in pituitary adenoma patients in order to determine their pathogenic role.

Method: Eleven missense and one nonsense, previously not studied AIP variants, were transfected into HEK 293 T cells to evaluate protein half-life in cycloheximide chase experiments. AIP protein expression at different time points were studied using western blotting. The results were then correlated with the clinical phenotype.

Results: A quarter of the studied variants showed a significant reduction in AIP protein half-life compared to the wild type. The protein degradation speed (K) of the positive control p.C238Y (0.289±0.087), and the variants p.A277P (0.289±0.087) and p.K241E (0.117±0.022) were significantly higher when compared to the WT (0.021±0.005). Table 1 shows all the variants studied and their clinical data.

Conclusion: Non-truncating variants in AIP with shorter half-life are likely to be pathogenic changes, while variants with normal half-life need further studies to determine pathogenicity.