Alternative titles; symbols
HGNC Approved Gene Symbol: AIP
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38) : 11:67,483,026-67,491,103 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | Pituitary adenoma 1, multiple types | 102200 | Autosomal dominant; Somatic mutation | 3 |
| Pituitary adenoma predisposition | 102200 | Autosomal dominant; Somatic mutation | 3 |
The aryl hydrocarbon receptor (AHR; 600253) is found in a multiprotein complex that includes the 90-kD heat shock protein (HSP90; see 140571). The AHR is a ligand-activated transcription factor that is a member of the basic helix-loop-helix PAS superfamily. In response to ligand binding in the cytosol, the AHR-HSP90 complex translocates to the nucleus where the molecular chaperone HSP90 dissociates and the activated AHR heterodimerizes with ARNT (126110). The resulting complex attains binding specificity for its cognate enhancer elements to regulate transcription of a variety of xenobiotic metabolizing enzymes.
The AHR-interacting protein (AIP) was originally cloned and designated XAP2 by Kuzhandaivelu et al. (1996) who used a yeast 2-hybrid system to identify proteins that interact with the hepatitis B virus (HBV) X protein. By use of a yeast 2-hybrid assay to detect proteins that interact with AHR in a ligand-dependent manner, Carver and Bradfield (1997) demonstrated interaction of AIP with AHR. They cloned an AIP cDNA, which they called ARA9, from a B-lymphocyte cDNA library. AIP encodes a deduced 330-amino acid protein with a molecular mass of approximately 37 kD. It contains regions of homology to the FK506-binding proteins FKBP4 (600611) and FKBP1A (186945). The predicted protein contains 3 C-terminal consensus tetratricopeptide repeat (TPR) domains similar to the TPR domains found in FKBP4 that may mediate protein-protein interactions. AIP was also identified by Meyer et al. (1998), who purified the AIP protein from the AHR cytosolic complex. Meyer et al. (1998) cloned simian AIP cDNA from a COS-1 cDNA library and found that it shares 98% amino acid sequence identity with human AIP.
Igreja et al. (2010) stated that the AIP gene contains 6 exons.
Using somatic cell hybrid analysis and FISH, Carver et al. (1998) mapped the AIP gene to chromosome 11q13.3.
Using Northern blot analysis, Kuzhandaivelu et al. (1996) detected a 1.25-kb AIP transcript in all 16 adult tissues tested with the exception of the liver. Expression was also detected in 3 cell lines, including cervical carcinoma, hepatocellular carcinoma, and choriocarcinoma cells. The lack of AIP expression in the liver led Kuzhandaivelu et al. (1996) to hypothesize that this may partially allow for the X protein to contribute to the hepatotropism of HBV. Using Northern blot analysis, Carver and Bradfield (1997) also detected expression of AIP in 15 human tissues examined, with highest levels of expression in heart, placenta, and skeletal muscle. Meyer et al. (1998) detected Aip expression in 11 mouse tissues examined by Northern blot analysis and RT-PCR. Using in situ hybridization in mouse embryos as early as embryonic day 9.5, Carver et al. (1998) detected Aip expression that was widespread and highest in the neuroepithelium, trigeminal ganglion, branchial arches, hepatic primordia, and the primitive gut. The expression remained widespread at embryonic day 13.5, with highest levels in the derivatives of the branchial arches, and expression was seen in adult lymphoid tissues.
Using indirect immunofluorescence, Kuzhandaivelu et al. (1996) localized both the HBV X protein and AIP to the cytoplasm in cultured HeLa cells. Subcellular fractionation confirmed the localization of AIP to the cytoplasmic fraction.
Using a GST fusion protein, Kuzhandaivelu et al. (1996) demonstrated that AIP binds to the HBV X protein. Using a series of X protein deletion mutants in a 2-hybrid system, they identified a 14-amino acid region (amino acids 13-26) important for binding AIP. This N-terminal region of the X protein was highly conserved among mammalian hepadnaviruses. Using cotransfection experiments, Kuzhandaivelu et al. (1996) showed that AIP is a specific cellular inhibitor of the X protein but not other viral transactivators.
Carver and Bradfield (1997) demonstrated that the interaction between AIP and AHR is enhanced in the presence of the ligand beta-naphthoflavone. Using a yeast expression system, Carver et al. (1998) demonstrated that AIP is able to enhance the ligand responsiveness of AHR. Coimmunoprecipitation experiments confirmed the interaction of AIP and AHR and suggested that AIP is present in AHR-HSP90 complexes. However, Meyer et al. (1998) demonstrated that AIP is not required for AHR-HSP90 complex formation in vitro. They also found that AIP does not directly interact with HSP90, suggesting that AIP becomes associated with the complex only in the presence of AHR.
Carver et al. (1998) attempted to define the domains required to form the AIP-HSP90-AHR complex using deletion analyses of both AIP and AHR. They demonstrated that the repressor domain of AHR, previously shown to contain domains required for HSP90 and ligand binding, is also required for interactions with AIP. The authors showed that the C-terminal TRP domains of AIP are necessary and sufficient for interactions with HSP90 and AHR and that AIP specifically associates with AHR-HSP90 complexes, but not with GR-HSP90 complexes. Also, AIP shows greater affinity for AHR-HSP90 complexes than FKBP4. Despite homology to FKBP4 and FKBP1A, Carver et al. (1998) were unable to detect AIP binding to FK506.
Leontiou et al. (2008) found that overexpression of wildtype AIP in human fibroblast and pituitary cell lines dramatically reduced cell proliferation, whereas mutant AIP lost this ability. Their functional evaluation of AIP mutations was consistent with a tumor suppressor role for AIP and its involvement in familial acromegaly. Leontiou et al. (2008) concluded that the abnormal expression and subcellular localization of AIP in sporadic pituitary adenomas (in cytoplasm rather than secretory vesicles) indicated deranged regulation of this protein during tumorigenesis.
Schernthaner-Reiter et al. (2018) found that endogenous Aip physically interacted and colocalized with the protein kinase A (PKA) subunits R1-alpha (PRKAR1A; 188830) and C-alpha (PRKACA; 601639) in the cytoplasm of rat mammosomatotropinoma cell line GH3. Fractionation analysis showed that all 3 proteins localized to cytoplasm and membranes of GH3 cells. Aip interacted with R1-alpha and C-alpha separately and in a 3-protein complex. Aip overexpression reduced PKA activity in GH3 cells. C-alpha overexpression stabilized both Aip and R1-alpha protein levels independent of PKA activity. Aip protein level was regulated by translation and degradation via the ubiquitin/proteasome pathway. Aip knockdown modestly increased PKA activity in GH3 cells. Further analysis revealed that Aip functionally interacted with PDE-dependent PKA pathway activity via Pde4 (600126).
In affected individuals from a large Finnish kindred with pituitary adenoma predisposition (PAP; see 102200), Vierimaa et al. (2006) identified a truncating mutation in the AIP gene (Q14X; 605555.0001). Five individuals had prolactinomas, 4 had somatotropinomas, and 2 had a mixed tumor comprising both cells. The Q14X mutation was also identified in 6 of 45 Finnish patients with acromegaly from a population-based cohort. In 2 Italian sibs with somatotropinomas, Vierimaa et al. (2006) identified a different truncating mutation (R304X; 605555.0003) in the AIP gene. Vierimaa et al. (2006) postulated that the phenotype represents a hereditary predisposition to pituitary adenomas with very low penetrance.
In 9 of 460 patients from Europe and the U.S. with pituitary adenomas, Georgitsi et al. (2007) identified 9 different mutations in the AIP gene (see, e.g., 605555.0004-605555.0006; 605555.0008). Eight patients had growth hormone-secreting adenomas and 1 had Cushing disease due to an ACTH-secreting adenoma.
Daly et al. (2007) studied the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA; see 102200) from 9 different countries. Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 AIP mutations; 9 of the mutations were novel. Tumors were significantly larger (p = 0.0005) and diagnosed at a younger age (p = 0.0006) in AIP mutation-positive versus mutation-negative subjects. Although somatotropinomas predominated among FIPA families with AIP mutations, mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also found. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations.
Igreja et al. (2010) identified AIP mutations in 11 of 38 FIPA families, including 3 with large deletions. The authors reviewed the clinical characteristics of these 38 families and 26 previously reported families (Leontiou et al., 2008), confirming that patients with AIP mutations had a lower mean age at diagnosis. Igreja et al. (2010) analyzed the various types of mutations that had been found in the AIP gene, and demonstrated that a promoter mutation showed reduced in vitro activity corresponding to lower expression in patient samples and that stimulation of the protein kinase-A (see 601639) pathway positively regulates the AIP promoter. Silent mutations led to abnormal splicing, resulting in truncated protein or reduced AIP expression. A 2-hybrid assay of protein-protein interactions of the 9 missense variants discovered to that time in the AIP gene showed variable disruption of AIP-phosphodiesterase-4A5 binding. Igreja et al. (2010) noted that overall, AIP mutations were implicated in 20 (31%) of the 64 families in their FIPA cohort.
Dal et al. (2020) identified 31 individuals with heterozygosity for the R304Q (605555.0008) mutation in the AIP gene in a large Danish kindred comprising 52 family members spanning 5 generations. Based on 2 cases of somatotropinomas among the mutation carriers, disease penetrance was 6%. In this cohort, there were 2 other individuals with acromegalic features, one of whom was heterozygous for R304Q. This led Dal et al. (2020) to perform whole-exome sequencing on 3 parent-child trios from within this kindred to look for cosegregating potential modifier mutations. They identified variants of interest in 2 genes, PDE11A (604961; c.893A-G, N298S) and ALG14 (612866; c.113G-T, p.S38I); the variants were reported in gnomAD with frequencies of 0.11% and 0.37% in non-Finnish Europeans, respectively. The clinical implications of the PDE11A and ALG14 candidate mutations were unknown.
Reclassified Variants
The R304Q variant in the AIP gene (605555.0008) that was identified in a patient with an ACTH-secreting pituitary adenoma by Georgitsi et al. (2007) has been reclassified as a variant of unknown significance.
In affected individuals from a large Finnish kindred with pituitary adenoma predisposition (PAP; see 102200), Vierimaa et al. (2006) identified a gln14-to-ter (Q14X) substitution in exon 1 of the AIP gene. Five individuals had prolactinomas, 4 had somatotropinomas and 2 had a mixed tumor comprising both cells. The Q14X mutation was also identified in 6 of 45 Finnish patients with acromegaly (PITA1; 102200) from a population-based cohort. Loss of heterozygosity at the AIP locus was observed in all 8 tumor tissues studied.
In a Finnish patient with acromegaly and pituitary adenoma (PITA1; 102200), Vierimaa et al. (2006) identified a G-to-A substitution in intron 3 of the AIP gene, affecting the splice acceptor site of exon 4.
In 2 Italian sibs with GH-secreting pituitary adenomas (PITA1; 102200), Vierimaa et al. (2006) identified an arg304-to-stop (R304X) substitution at codon 304 in the AIP gene. This mutation was not found in 203 Caucasian controls from the U.K. or CEPH or 52 local blood donors.
Daly et al. (2007) identified the R304X mutation in 3 affected members of another Italian family with GH-secreting pituitary adenomas and acromegaly.
Chahal et al. (2011) identified the same nonsense mutation in DNA extracted from teeth of an Irish patient who lived from 1761 to 1783 (Charles Byrne, 'The Irish Giant'; Bergland, 1965), whose skull had been noted by Harvey Cushing to possess an enlarged pituitary fossa. Four contemporary northern Irish families who presented with gigantism, acromegaly, or prolactinoma had the same mutation and haplotype associated with the mutated gene. Using coalescent theory, Chahal et al. (2011) inferred that these persons share a common ancestor who lived about 57 to 66 generations earlier. In the 4 families, Chahal et al. (2011) identified 51 carriers of the mutation but only 14 affected subjects. The level of penetrance was difficult to establish since information on genetic and clinical data were incomplete.
In a 20-year-old German man with acromegaly secondary to a pituitary adenoma (PITA1; 102200), Georgitsi et al. (2007) identified a heterozygous 6-bp deletion (66delAGGAGA) in exon 1 of the AIP gene. Tumor tissue showed loss of the normal AIP allele. The patient had a family history of acromegaly.
In an 8-year-old boy with a GH-secreting pituitary adenoma (PITA1; 102200), Georgitsi et al. (2007) identified a heterozygous 1-bp insertion (824insA) in exon 6 of the AIP gene. Tumor tissue showed loss of the normal AIP allele.
In an 18-year-old man from Spain with acromegaly secondary to a pituitary adenoma (PITA1; 102200), Georgitsi et al. (2007) identified a heterozygous 1-bp deletion (542delT) in exon 4 of the AIP gene. He had a family history of acromegaly.
In 4 affected members of a Brazilian family with pituitary tumor predisposition (PAP; see 102200), Toledo et al. (2007) identified heterozygosity for an 804A-C transversion in the AIP gene, resulting in a tyr268-to-ter (Y268X) substitution predicted to generate a protein lacking 2 conserved domains. The 4 affected members included 2 sibs with early-onset acromegaly, a 41-year-old sib with a nonsecreting microadenoma and no clinical features of disease, and his 3-year-old son. No changes were found in 14 unaffected at-risk relatives or 92 healthy controls.
This variant, formerly titled PITUITARY ADENOMA 1, ACTH-SECRETING, has been reclassified based on review of the gnomAD database by Hamosh (2024).
In a 26-year-old Polish patient with Cushing disease due to an ACTH-secreting pituitary adenoma (PITA1; 102200), Georgitsi et al. (2007) identified a heterozygous c.911G-A transition in exon 6 of the AIP gene, resulting in an arg304-to-gln (R304Q) substitution.
In a large Danish kindred comprising 52 family members spanning 5 generations, Dal et al. (2020) identified 31 individuals with heterozygosity for the R304Q mutation. Based on 2 cases of somatotropinomas among the mutation carriers, the disease penetrance was 6%. Two individuals with homozygosity for R304Q were reported in the gnomAD database.
Hamosh (2024) noted that the R304Q variant was present in 437 of 278,694 alleles and in 2 homozygotes, with an allele frequency of 0.001568, in the gnomAD database (v2.1). She stated that R304Q may be a low penetrance susceptibility allele.
In a 24-year-old man with acromegaly due to a GH-secreting adenoma (PITA1; 102200), Barlier et al. (2007) identified a heterozygous C-to-T transition in exon 1 of the AIP gene, resulting in an arg22-to-ter (R22X) substitution. The tumor tissue showed loss of heterozygosity at the AIP locus. The patient had an aggressive macroadenoma that was resistant to somatostatin agonist therapy. He also required radiotherapy postoperatively.
Barlier, A., Vanbellinghen, J.-F., Daly, A. F., Silvy, M., Jaffrain-Rea, M.-L., Trouillas, J., Tamagno, G., Cazabat, L., Bours, V., Brue, T., Enjalbert, A., Beckers, A. Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas. J. Clin. Endocr. Metab. 92: 1952-1955, 2007. [PubMed: 17299063] [Full Text: https://doi.org/10.1210/jc.2006-2702]
Bergland, Richard M. New information concerning the Irish Giant. J. Neurosurg. 23: 265-269, 1965. [PubMed: 5320367] [Full Text: https://doi.org/10.3171/jns.1965.23.3.0265]
Carver, L. A., Bradfield, C. A. Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo. J. Biol. Chem. 272: 11452-11456, 1997. [PubMed: 9111057] [Full Text: https://doi.org/10.1074/jbc.272.17.11452]
Carver, L. A., LaPres, J. J., Jain, S., Dunham, E. E., Bradfield, C. A. Characterization of the Ah receptor-associated protein, ARA9. J. Biol. Chem. 273: 33580-33587, 1998. [PubMed: 9837941] [Full Text: https://doi.org/10.1074/jbc.273.50.33580]
Chahal, H. S., Stals, K., Unterlander, M., Balding, D. J., Thomas, M. G., Kumar, A. V., Besser, G. M., Atkinson, A. B., Morrison, P. J., Howlett, T. A., Levy, M. J., Orme, S. M., Akker, S. A., Abel, R. L., Grossman, A. B., Burger, J., Ellard, S., Korbonits, M. AIP mutation in pituitary adenomas in the 18th century and today. New Eng. J. Med. 364: 43-50, 2011. [PubMed: 21208107] [Full Text: https://doi.org/10.1056/NEJMoa1008020]
Dal, J., Nielsen, E. H., Klose, M., Feldt-Rasmussen, U., Andersen, M., Vang, S., Korbonits, M., Jorgensen, J. O. L. Phenotypic and genotypic features of a large kindred with a germline AIP variant. Clin. Endocr. 93: 146-153, 2020. [PubMed: 32324286] [Full Text: https://doi.org/10.1111/cen.14207]
Daly, A. F., Vanbellinghen, J.-F., Khoo, S. K., Jaffrain-Rea, M.-L., Naves, L. A., Guitelman, M. A., Murat, A., Emy, P., Gimenez-Roqueplo, A.-P., Tamburrano, G., Raverot, G., Barlier, A., and 32 others. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J. Clin. Endocr. Metab. 92: 1891-1896, 2007. [PubMed: 17244780] [Full Text: https://doi.org/10.1210/jc.2006-2513]
Georgitsi, M., Raitila, A., Karhu, A., Tuppurainen, K., Makinen, M. J., Vierimaa, O., Paschke, R., Saeger, W., van der Luijt, R. B., Sane, T., Robledo, M., De Menis, E., Weil, R. J., Wasik, A., Zielinski, G., Lucewicz, O., Lubinski, J., Launonen, V., Vahteristo, P., Aaltonen, L. A. Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Proc. Nat. Acad. Sci. 104: 4101-4105, 2007. [PubMed: 17360484] [Full Text: https://doi.org/10.1073/pnas.0700004104]
Hamosh, A. Personal Communication. Baltimore, Md. 1/17/2024.
Igreja, S., Chahal, H. S., King, P., Bolger, G. B., Srirangalingam, U., Guasti, L., Chapple, J. P., Trivellin, G., Gueorguiev, M., Guegan, K., Stals, K., Khoo, B., Kumar, A. V., Ellard, S., Grossman, A. B., Korbonits, M., International FIPA Consortium. Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum. Mutat. 31: 950-960, 2010. [PubMed: 20506337] [Full Text: https://doi.org/10.1002/humu.21292]
Kuzhandaivelu, N., Cong, Y.-S., Inouye, C., Yang, W.-M., Seto, E. XAP2, a novel hepatitis B virus X-associated protein that inhibits X transactivation. Nucleic Acids Res. 24: 4741-4750, 1996. [PubMed: 8972861] [Full Text: https://doi.org/10.1093/nar/24.23.4741]
Leontiou, C. A., Gueorguiev, M., van der Spuy, J., Quinton, R., Lolli, F., Hassan, S., Chahal, H. S., Igreja, S. C., Jordan, S., Rowe, J., Stolbrink, M., Christian, H. C., and 23 others. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J. Clin. Endocr. Metab. 93: 2390-2401, 2008. [PubMed: 18381572] [Full Text: https://doi.org/10.1210/jc.2007-2611]
Meyer, B. K., Pray-Grant, M. G., Vanden Heuvel, J. P., Perdew, G. H. Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity. Molec. Cell. Biol. 18: 978-988, 1998. [PubMed: 9447995] [Full Text: https://doi.org/10.1128/MCB.18.2.978]
Schernthaner-Reiter, M. H., Trivellin, G., Stratakis, C. A. Interaction of AIP with protein kinase A (cAMP-dependent protein kinase). Hum. Molec. Genet. 27: 2604-2613, 2018. [PubMed: 29726992] [Full Text: https://doi.org/10.1093/hmg/ddy166]
Toledo, R. A., Lourenco, D. M., Jr., Liberman, B., Cunha-Neto, M. B. C., Cavalcanti, M. G., Moyses, C. B., Toledo, S. P. A., Dahia, P. L. M. Germline mutation in the aryl hydrocarbon receptor interacting protein gene in familial somatotropinoma. J. Clin. Endocr. Metab. 92: 1934-1937, 2007. [PubMed: 17341560] [Full Text: https://doi.org/10.1210/jc.2006-2394]
Vierimaa, O., Georgitsi, M., Lehtonen, R., Vahteristo, P., Kokko, A., Raitila, A., Tuppurainen, K., Ebeling, T. M. L., Salmela, P. I., Paschke, R., Gundogdu, S., De Menis, E., Makinen, M. J., Launonen, V., Karhu, A., Aaltonen, L. A. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312: 1228-1230, 2006. [PubMed: 16728643] [Full Text: https://doi.org/10.1126/science.1126100]