AIP – Acromegaly

Germline heterozygous mutations in the aryl hydrocarbon receptor–interacting protein (AIP) gene cause autosomal dominant predisposition to acromegaly due to GH-secreting pituitary adenomas. Over 460 unselected and young-onset acromegaly patients have been screened, yielding AIP variants in 5–7% of cases ([PMID:17360484]; [PMID:25093619]). Segregation analysis in 12 kindreds demonstrated co-segregation of pathogenic truncating variants with disease in 4 affected relatives ([PMID:24423289]).

Inheritance is autosomal dominant with incomplete penetrance. Case series encompass >200 probands harboring truncating (nonsense, frameshift, splice) and pathogenic missense variants. Recurrent founder alleles such as c.241C>T (p.Arg81Ter) and c.685C>T (p.Gln229Ter) have been reported in multiple families ([PMID:20454499]; [PMID:24996936]). The variant spectrum includes 18 truncating and 12 missense changes disrupting the C-terminal TPR domain or the N-terminal α-helical repeats.

Functional studies support a haploinsufficiency mechanism. Wild-type AIP overexpression suppresses forskolin-induced cAMP signaling and GH release in GH3 cells, whereas knockdown or mutant AIP enhances cAMP concentrations and cell proliferation ([PMID:23702468]; [PMID:24662816]). Structural analysis of the TPR domain showed that C-terminal α-7 helix mutations (e.g., p.Arg304Gln, p.Arg325Gln) selectively abrogate client protein binding without affecting HSP90 interaction ([PMID:23300914]).

Somatostatin analog (SSA) treatment upregulates AIP and ZAC1 expression in vivo; AIP-mutant adenomas demonstrate attenuated SSA responsiveness, correlating with lower AIP immunostaining and resistance to medical therapy ([PMID:22659247]). Proteasomal degradation assays reveal that many missense AIP variants undergo rapid turnover, linking protein half-life to age at diagnosis and severity of acromegaly ([PMID:27253664]).

Conflicting evidence exists for the common p.Arg304Gln variant. Population data show R304Q at 0.3% frequency with absence of LOH in tumors and older age at onset, leading to likely benign reclassification ([PMID:40070360]).

In summary, AIP is a well‐established tumor suppressor in pituitary somatotrophs; loss-of-function variants confer a strong risk for early-onset acromegaly. Diagnostic testing for pathogenic truncating and missense AIP variants guides surveillance in at-risk relatives. Key take-home: AIP mutation status refines clinical management, predicts SSA responsiveness, and directs family screening.

References

• Proceedings of the National Academy of Sciences • 2007 • Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations PMID:17360484
• PLoS One • 2014 • AIP mutations in young patients with acromegaly and the Tampico Giant: the Mexican experience PMID:25093619
• The Journal of Clinical Endocrinology & Metabolism • 2014 • Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation PMID:24423289
• Endocrine-Related Cancer • 2012 • Aip regulates cAMP signalling and GH secretion in GH3 cells PMID:23702468
• PLoS One • 2012 • Structure of the TPR domain of AIP: lack of client protein interaction with the C-terminal α-7 helix of the TPR domain of AIP is sufficient for pituitary adenoma predisposition PMID:23300914
• The Journal of Clinical Endocrinology & Metabolism • 2012 • Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway PMID:22659247
• Oncogene • 2015 • AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling PMID:24662816
• The Journal of Clinical Endocrinology & Metabolism • 2016 • Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations PMID:27253664
• European Journal of Endocrinology • 2025 • Reassessing the role of the p.(Arg304Gln) missense AIP variant in pituitary tumorigenesis PMID:40070360

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