Characterization of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Mutations in Familial Isolated Pituitary Adenoma Families

Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom EC1M 6BQ.
Human Mutation (Impact Factor: 5.14). 08/2010; 31(8):950-60. DOI: 10.1002/humu.21292
Source: PubMed


Familial isolated pituitary adenoma (FIPA) is an autosomal dominant condition with variable genetic background and incomplete penetrance. Germline mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene have been reported in 15-40% of FIPA patients. Limited data are available on the functional consequences of the mutations or regarding the regulation of the AIP gene. We describe a large cohort of FIPA families and characterize missense and silent mutations using minigene constructs, luciferase and beta-galactosidase assays, as well as in silico predictions. Patients with AIP mutations had a lower mean age at diagnosis (23.6+/-11.2 years) than AIP mutation-negative patients (40.4+/-14.5 years). A promoter mutation showed reduced in vitro activity corresponding to lower mRNA expression in patient samples. Stimulation of the protein kinase A-pathway positively regulates the AIP promoter. Silent mutations led to abnormal splicing resulting in truncated protein or reduced AIP expression. A two-hybrid assay of protein-protein interaction of all missense variants showed variable disruption of AIP-phosphodiesterase-4A5 binding. In summary, exonic, promoter, splice-site, and large deletion mutations in AIP are implicated in 31% of families in our FIPA cohort. Functional characterization of AIP changes is important to identify the functional impact of gene sequence variants.

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    • "Nonsense and frameshift mutations lead to premature stop codons with a resultant truncated protein, whereas missense mutations tend to affect the tetratricopeptide repeat domains and the terminal α-helix. Whole gene deletions have also been identified, suggesting the use of a multiple ligation-dependent probe amplification method for patients with FIPA in whom sequencing fails to identify abnormalities (34),(35),(36). Mutations in codons R304, R271, and R81 have been reported in independent families with FIPA, indicating possible hotspots. No genotype–phenotype correlations have been observed to date in patients with AIP-mutated FIPA (37). "
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    ABSTRACT: Pituitary adenomas represent a group of functionally diverse neoplasms with relatively high prevalence in the general population. Most occur sporadically, but inherited genetic predisposing factors are increasingly recognized. Familial isolated pituitary adenoma is a recently defined clinical entity, and is characterized by hereditary presentation of pituitary adenomas in the absence of clinical and genetic features of syndromic disease such as multiple endocrine neoplasia type 1 and Carney complex. Familial isolated pituitary adenoma is inherited in an autosomal dominant manner and accounted for approximately 2-3% of pituitary tumors in some series. Germline mutations in the aryl-hydrocarbon interacting protein gene are identified in around 25% of familial isolated pituitary adenoma kindreds. Pituitary adenomas with mutations of the aryl-hydrocarbon interacting protein gene are predominantly somatotropinomas and prolactinomas, but non-functioning adenomas, Cushing disease, and thyrotropinoma may also occur. These tumors may present as macroadenomas in young patients and are often relatively difficult to control. Furthermore, recent evidence indicates that aryl-hydrocarbon interacting protein gene mutations occur in >10% of patients with sporadic macroadenomas that occur before 30 years of age, and in >20% of children with macroadenomas. Genetic screening for aryl-hydrocarbon interacting protein gene mutations is warranted in selected high-risk patients who may benefit from early recognition and follow-up.
    Full-text · Article · Apr 2012 · Clinics (São Paulo, Brazil)
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    • "remained statistically significant predictors of disease control. Germline mutations in the AIP gene are found in familial and early-onset pituitary adenoma setting, with a predomination of somatotropinomas in the mutated gene cases (Igreja et al. 2010, Tichomirowa et al. 2011). The AIP-mutated patients have smaller decreases in GH and IGF1 levels as well as less tumor shrinkage with SRL therapy (Leontiou et al. 2008, Daly et al. 2010, Pinho et al. 2010). "
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    ABSTRACT: Context: Somatotropinomas harboring AIP mutations respond less to somatostatin receptor ligands (SRL). Therefore, AIP expression may be a new predictor of response to SRL therapy. Objectives: To evaluate whether AIP expression is a predictor of acromegaly control with octreotide LAR (OCT-LAR) therapy independent of the expression of somatostatin receptor (SSTR) subtype 2. Methods: AIP and SSTR2 expression were analyzed by immunohistochemistry. AIP immunopositivity was graded according to staining pattern and intensity. SSTR2 expression was considered high when >25% of cells were immunostained. Patients were considered controlled when they exhibited normal age-matched IGF-I and basal GH <1.0 ng/mL. Results: Thirty-five sporadic somatotropinomas without AIP mutation were studied. Fifteen (43%) patients were controlled with OCT-LAR. None of the patients with SSTR2A expression levels <25% were controlled. Four out of 18 tumors (22%) with low AIP expression were controlled with OCT-LAR treatment, whereas 11 out of 17 (65%) patients with high AIP expression reached a biochemically controlled disease state (p=0.013). The control rate in the patients who presented with high AIP and SSTR2 expression levels was 79%. The combination of both tests yielded an accuracy of 80%. After multivariate analysis, both SSTR2A (p=0.02) and AIP (p=0.02) were predictors of disease control. Conclusion: The AIP expression level is a new predictor of acromegaly control with OCT-LAR therapy in sporadic somatotropinomas without AIP mutations independent of SSTR2 expression. In addition, when both are used in conjunction, it is possible to predict patient responses to OCT-LAR therapy with a higher accuracy.
    Full-text · Article · Mar 2012 · Endocrine Related Cancer
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    • "Recent studies suggest the involvement of XAP2 in a wide range of biological processes with tumorigenic outcome [28]. For example, disruption of XAP2 is observed in patients with family history of pituitary tumors [6], [29]. However, the mechanisms behind the tumor suppressive-activity of XAP2 have not been clarified yet. "
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    ABSTRACT: XAP2 (also known as aryl hydrocarbon receptor interacting protein, AIP) is originally identified as a negative regulator of the hepatitis B virus X-associated protein. Recent studies have expanded the range of XAP2 client proteins to include the nuclear receptor family of transcription factors. In this study, we show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. Interestingly, we show that XAP2 downregulates the E₂-dependent transcriptional activation in an estrogen receptor (ER) isoform-specific manner: XAP2 inhibits ERα but not ERβ-mediated transcription. Thus, knockdown of intracellular XAP2 levels leads to increased ERα activity. XAP2 proteins, carrying mutations in their primary structures, loose the ability of interacting with ERα and can no longer regulate ER target gene transcription. Taken together, this study shows that XAP2 exerts a negative effect on ERα transcriptional activity and may thus prevent ERα-dependent events.
    Full-text · Article · Oct 2011 · PLoS ONE
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