Aryl Hydrocarbon Receptor-interacting Protein Gene Research Articles

The clinical and therapeutic profiles of prolactinomas associated with germline pathogenic variants in the aryl hydrocarbon receptor interacting protein (AIP) gene.

Prolactinomas are the most frequent type of pituitary adenoma encountered in clinical practice. Dopamine agonists (DA) like cabergoline typically provide sign/ symptom control, normalize prolactin levels and decrease tumor size in most patients. DA-resistant prolactinomas are infrequent and can occur in association with some genetic causes like MEN1 and pathogenic germline variants in the AIP gene (AIPvar). We compared the clinical, radiological, and therapeutic characteristics of AIPvar-related prolactinomas (n=13) with unselected hospital-treated prolactinomas ("unselected", n=41) and genetically-negative, DA-resistant prolactinomas (DA-resistant, n=39). AIPvar-related prolactinomas occurred at a significantly younger age than the unselected or DA-resistant prolactinomas (p<0.01). Males were more common in the AIPvar (75.0%) and DA- resistant (49.7%) versus unselected prolactinomas (9.8%; p<0.001). AIPvar prolactinomas exhibited significantly more frequent invasion than the other groups (p<0.001) and exhibited a trend to larger tumor diameter. The DA-resistant group had significantly higher prolactin levels at diagnosis than the AIPvar group (p<0.001). Maximum DA doses were significantly higher in the AIPvar and DA-resistant groups versus unselected. DA-induced macroadenoma shrinkage (>50%) occurred in 58.3% in the AIPvar group versus 4.2% in the DA-resistant group (p<0.01). Surgery was more frequent in the AIPvar and DA- resistant groups (43.8% and 61.5%, respectively) versus unselected (19.5%: p<0.01). Radiotherapy was used only in AIPvar (18.8%) and DA-resistant (25.6%) groups. AIPvar confer an aggressive phenotype in prolactinomas, with invasive tumors occurring at a younger age. These characteristics can help differentiate rare AIPvar related prolactinomas from DA-resistant, genetically-negative tumors.

Low frequency of AIP mutations in patients with young-onset sporadic pituitary macroadenomas

PurposeMutations in the aryl hydrocarbon receptor interacting protein (AIP) gene cause familial isolated pituitary adenomas (FIPA). AIP mutations have also been found in patients with apparently sporadic pituitary adenomas, particularly in young patients with large adenomas. The aim of this study was to determine the frequency of AIP germline mutations in patients with young-onset sporadic pituitary macroadenomas.MethodsThe AIP gene was sequenced in 218 Portuguese patients with sporadic pituitary macroadenomas diagnosed before the age of 40 years.ResultsHeterozygous rare sequence variants in AIP were identified in 18 (8.3%) patients. However, only four (1.8%) patients had pathogenic or likely pathogenic variants. These consisted of two already known mutations (p.Arg81* and p.Leu115Trpfs*41) and two novel mutations (p.Glu246*, p.Ser53Thrfs*36). All four patients had GH-secreting adenomas diagnosed between the ages of 14 and 25 years. The frequency of AIP pathogenic or likely pathogenic variants in patients under the age of 30 and 18 years was 3.4% and 5.0%, respectively.ConclusionThe frequency of AIP mutations in this cohort was lower than in other studies. Previous reports may have overestimated the contribution of AIP mutations due to the inclusion of genetic variants of uncertain significance. The identification of novel AIP mutations expands the known spectrum of genetic causes of pituitary adenomas and may help understand the role of AIP mutations in the molecular mechanisms underlying pituitary tumorigenesis.

AIP gene germline variants in adult Polish patients with apparently sporadic pituitary macroadenomas.

Up to 5% of all pituitary tumors are hereditary e.g. due to MEN1 or aryl hydrocarbon receptor-interacting protein (AIP) genes mutations. The study was aimed at the assessment of the frequency and characteristics of AIP-mutation related tumors in patients with apparently sporadic pituitary macroadenomas in the Polish population. The study included 131 patients (57 males, 74 females; median age 42 years) diagnosed with pituitary macroadenomas, and with a negative family history of familial isolated pituitary adenoma (FIPA) or multiple endocrine neoplasia type 1 (MEN1) syndromes. Sanger sequencing was used for the assessment of AIP gene variants. The study was approved by the Ethics Board of JUMC. AIP variants were identified in five of the 131 included subjects (3.8%): one diagnosed with Cushing's disease, two with acromegaly, and two with non-secreting adenomas. Patients harboring hereditary AIP gene alterations did not differ from the rest of the study group in median age at diagnosis (41.0 vs. 42.5 years, P=0.8), median largest tumor diameter (25 vs. 24mm, P=0.6), gender distribution (60.0% vs. 56.3% females, P=0.8), secreting tumor frequency (60.0% vs. 67.5%, P=0.7), or acromegaly diagnosis frequency (40.0% vs.37.3%, P=0.9). In our series of apparently sporadic pituitary macroadenomas, AIP gene variant carriers did not differ substantially from patients with negative genetic testing. A risk factor-centred approach to AIP genetic screening may result in missing germline variants. Considering the clinical impact of such genetic variants and their relatively low penetrance, it is, however, doubtful if general genetic screening benefits the whole cohort of pituitary macroadenoma patients and their families.

Studying the genotype of Aryl Hydrocarbon Receptor-Interacting Protein (AIP) Gene (rs641081C&gt;A) in ‎Iraqi Samples with Acromegaly Pituitary Adenoma

Pituitary adenomas are the anterior pituitary tumors. Patients with an Aryl Hydrocarbon Receptor-Interacting Protein (AIP) mutation (AIP- mut) tend to have more aggressive tumors occurring at a younger age. Single nucleotide polymorphisms (SNPs) in many studies have been related to metabolic comorbidities in the general population. Study aims investigated the role of AIP gene SNPs with susceptibility to acromegaly pituitary- adenoma, with levels of LH, FSH, TSH, Testosterone, IGF1,GH, FT4 , Prolactin hormones and blood sugar levels. The study ‎was conducted on a group of acromegaly patients, including 50 patients) both Genders( with ‎hyperplasia of the ends, and apparently healthy control group. Genotyping of AIP gene SNP (rs641081C &gt;A‎) was indicated significant differences in frequency percentage between the study groups. The frequency of heterozygous CA genotype was significantly (p&lt;0.01) higher in the patients' group when compared with control. The Means of IGF1, GH, prolactin, testosterone, and FBS were significantly ‎higher in patients at first treatment than that in control.‎ While,‎ the means of IGF1, GH, prolactin, and testosterone increased significantly in patients at last treatment than control. Patients mean level of TSH decreased significantly at last ‎treatment. No significant differences (P ≥ 0.05) were detected between study ‎groups in all other values.‎ The Means of IGF1, GH, and prolactin at first and last treatment were significantly decreased, while LH ‎was significantly increased at last treatment. In ‎patients with heterozygous mutant and wild genotype, means of IGF1, GH, and ‎prolactin decreased significantly at last treatment compared ‎to first treatment. ‎In this study heterozygous rs641081C&gt;A showed a risk factor for susceptibility of acromegaly. Also, serum IGF1, GH, prolactin, were affected by the SNP of AIP gene within carriers of genotypes of rs641081C&gt;A. IGF1, prolactin and GH ‎decreased significantly at last treatment compared to first treatment.

Prolactinoma in Two Brothers - Unidentified Genetic Cause Versus Co-Incidence?

Background: Most prolactinomas occur sporadically. Familial prolactinomas are uncommon. Clinical Case(s): A 35 YO male with no significant past medical history presented to endocrine clinic with c/o fatigue, decreased libido, and erectile dysfunction. Labs showed low total testosterone of 177 ng/dl (normal range 250-1100 ng/dl), low free testosterone of 19.9 pg/ml (normal range 46-224), low LH 1.1 (normal range 1.5-9.3 mIU/ml) with elevated prolactin of 47 ng/ml (normal range 2-18). MRI pituitary showed a 4.2x4x6 mm pituitary microadenoma. Physical exam was unremarkable except for obese body habitus. No known family history of MEN syndromes or parathyroid /calcium disorders. Dopamine agonist therapy resulted in significant improvement in testosterone levels, fatigue, and libido. One year after patient’s diagnosis his 32 YO younger brother was evaluated for c/o fatigue, inability to lose weight, left breast enlargement, galactorrhea, and decreased libido. Work up showed markedly elevated prolactin levels of 2405 ng/ml (normal range 4-15), decreased total testosterone of 70 ng/dl (normal range 249-836), low free testosterone of 4.8 pg/ml (normal range 8.7 to 25.1), FSH <0.1 mIU/ml (normal range 1.4-15.4), LH < 0.1 mIU/ml (normal range 1.7-8.6). MRI Pituitary showed a 25x28x20 mm pituitary macroadenoma invading the right cavernous sinus, encasing the right internal carotid artery, and abutting the optic chiasma. Our patient had genetic testing done for sequencing and deletion/duplication analysis of MEN1 and AIP (Aryl hydrocarbon receptor interacting protein) genes—two well identified causes of familial pituitary adenomas—and tested negative for both. His brother was treated with dopamine agonists with marked improvement in Prolactin to undetectable levels within a few weeks. His energy levels, headaches, and sexual function improved and galactorrhea resolved. However, testosterone levels remained below normal range even after 11 months, despite normal prolactin levels. Discussion: Prolactinomas are the most common functional pituitary adenomas, majority of them sporadic. Familial pituitary adenomas in non-syndromic form are rare. Familial isolated pituitary adenoma (FIPA) and Multiple endocrine neoplasia type 1(MEN 1) are two main causes of familial pituitary adenomas. In FIPA, pituitary adenomas occur as a result of mutations or deletions in aryl hydrocarbon receptor interacting protein gene (AIP). Identifying these mutations is important as pituitary adenomas in FIPA tend to be more aggressive, present at a younger age and are resistant to treatment. Our patient tested negative for both MEN 1 and AIP gene mutations. Whether our patient has an unidentified genetic cause or whether it was a coincidence that two brothers have prolactinomas is unclear.

Genetics, clinical features and outcomes of non-syndromic pituitary gigantism: experience of a single center from Sao Paulo, Brazil.

Non-syndromic pituitary gigantism (PG) is a very rare disease. Aryl hydrocarbon receptor-interacting protein (AIP) and G protein-coupled receptor 101 (GPR101) genetic abnormalities represent important etiologic causes of PG and may account for up to 40% of these cases. Here, we aimed to characterize the clinical and molecular findings and long-term outcomes in 18 patients (15 males, three females) with PG followed at a single tertiary center in Sao Paulo, Brazil. Genetic testing for AIP and GPR101 were performed by DNA sequencing, droplet digital PCR and array comparative genomic hybridization (aCGH). Pathogenic variants in the AIP gene were detected in 25% of patients, including a novel variant in splicing regulatory sequences which was present in a sporadic male case. X-LAG due to GPR101 microduplication was diagnosed in two female patients (12.5%). Of interest, these patients had symptoms onset by age 5 and 9years old and diagnosis at 5 and 15years, respectively. X-LAG, but not AIP, patients had a significantly lower age of symptoms onset and diagnosis and a higher height Z-score when compared to non-X-LAG. No other differences in clinical features and/or treatment outcomes were observed among PG based on their genetic background. We characterize the clinical and molecular findings and long-term outcome of the largest single-center PG cohort described so far.

SNPs of miR-23b, miR-107 and HMGA2 and their Relations with the Response to Medical Treatment in Acromegaly Patients.

Acromegaly is a chronic disease of increased growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels induced by a pituitary adenoma. HMGA2 (high mobility group A2) and AIP (aryl hydrocarbon receptor-interacting protein) expression levels are related to GH-secreting adenomas, and also a response to Somatostatin Analogs (SSAs). We studied SNPs in miR-107 and miR-23b that related with AIP and HMGA2 genes respectively and control their expression, and also SNP in the 3'UTR of HMGA2 gene. Our aim was to investigate genotype distributions of the studied SNPs, as well as the possible relationship between disease and/or response to SSAs treatment in patients with acromegaly. Genotypes were determined by qRT-PCR method from DNA materials obtained blood samples of acromegaly patients (141) and healthy individuals (99). The genotype distributions of patients and healthy groups, as well as the relationship between the clinical data of the disease and genotypes were statistically compared. In acromegaly patients with T-allele, p53 expression (p=0.049) was significantly higher. In patients with CT+TT genotype and T-allele who were responder to SSA-treatment Ki-67 index (respectively p=0.019, p=0.020 respectively) was higher. We did not observe the genotypes for miR-23b and miR-107 polymorphisms in the patients and control group of Turkish population. The genetic variations of the miRNAs genes related with HMGA2 and AIP genes were not seen in our study. Although there is no relationship between HMGA2-rs1351394 polymorphism and acromegaly disease, T allele was associated with some clinical features related to adenoma in patients with acromegaly.

Differentiated thyroid carcinoma in sporadic and familial presentations of acromegaly: A case series

BackgroundIn acromegaly, chronic growth hormone (GH) and insulin-like growth factor-1 (IGF-1) exacerbate comorbidities in multiple organs. Differentiated thyroid carcinoma (DTC) has been reported as being a comorbid condition in acromegaly. Acromegaly is usuallysporadic, but 5% of cases may be genetic. The most frequent inheritable form of acromegaly is related to germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Epidemiological data on the relationship between active acromegaly, its familial forms and DTC are sparse. We present the investigation of a FIPA family (familial isolated pituitary adenoma) with homogeneous acromegaly and 6 sporadic acromegaly patients with DTC. Patients and methodsA study of 59 acromegaly patients assessed thyroid nodules on ultrasound and fine-needle aspiration biopsy following the ATA 2015 criteria. We diagnosed 7 differentiated thyroid carcinomas. Resected thyroid carcinoma tissues were stained using an anti-AIP antibody. Analysis of germline and tumor-derived DNA for variants in the AIP and MEN1 genes were performed in the FIPA kindred. ResultsWe describe one FIPA patient and 6 sporadic acromegaly cases with DTC. The FIPA family (AIP mutation negative) consisted of two sisters, one of whom had a DTC with intermediate risk and incomplete structural response to therapy. In our study, DTC in sporadic acromegaly had a low recurrence rate (6/6), and excellent response to therapy (6/6). Immunohistochemistry for AIP showed similar or increased staining intensity in DTC versus normal thyroid tissue. ConclusionIn our cohort of sporadic and familial forms of acromegaly with DTC, AIP did not appear to influence thyroid cancer progression.

The role of AIP variants in pituitary adenomas and concomitant thyroid carcinomas in the Netherlands: a nationwide pathology registry (PALGA) study

PurposeGermline mutations in the aryl-hydrocarbon receptor interacting protein (AIP) have been identified often in the setting of familial isolated pituitary adenoma (FIPA). To date there is no strong evidence linking germline AIP mutations to other neoplasms apart from the pituitary. Our primary objective was to investigate the prevalence of AIP gene mutations and mutations in genes that have been associated with neuroendocrine tumors in series of tumors from patients presenting with both pituitary adenomas and differentiated thyroid carcinomas (DTCs).MethodsPathology samples were retrieved from all pituitary adenomas in patients with concomitant DTCs, including one with a known germline AIP variant. Subsequently, two additional patients with known germline AIP variants were included, of which one presented only with a follicular thyroid carcinoma (FTC).ResultsIn total, 17 patients (14 DTCs and 15 pituitary adenomas) were investigated by targeted next generation sequencing (NGS). The pituitary tumor samples revealed no mutations, while among the thyroid tumor samples BRAF (6/14, 42.9%) was the most frequently mutated gene, followed by NRAS (3/11, 27.3%). In one AIP-mutated FIPA kindred, the AIP-variant c.853C>T; p.Q285* was confirmed in the FTC specimen, including evidence of loss of heterozygosity (LOH) at the AIP locus in the tumor DNA.ConclusionAlthough most observed variants in pituitary adenomas and DTCs were similar to those of sporadic DTCs, we confirmed in one AIP mutation-positive case the AIP-variant and LOH at this locus in an FTC specimen, which raises the potential role of the AIP mutation as a rare initiating event.

Pituitary gigantism: a case series from Hospital de San José (Bogotá, Colombia).

Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities. Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016. All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma. This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.

SAT-462 AIP Mutation-Positive Patients with Somatotropinomas End up Taller and Requiring Radiotherapy More Often Compared to AIP Mutation-Negative Patients: Data from 784 Familial and Young-Onset Cases

Introduction: Germline mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) are responsible for up to 50% of familial isolated pituitary adenoma (FIPA) kindreds affected only with somatotropinomas. AIP mutation-positive (AIPmut) somatotropinomas present earlier, more aggressively and are often more resistant to therapy. We aimed to further characterise AIPmut somatotropinomas in terms of clinical features and outcomes. Methods: We studied AIPmut somatotropinomas which presented clinically; prospectively-diagnosed AIPmut somatotropinomas (i.e. somatotropinomas diagnosed following genetic and clinical screening) were excluded from the analysis. Indications for AIP genetic testing were: i) FIPA patients, ii) sporadic pituitary GH-secreting macroadenomas with disease onset <30y, or iii) GH-secreting microadenomas with age of onset <18y. Results: Out of 784 patients with somatotropinomas included in our study, 139 had an AIP mutation (17.7%). In comparison to AIP mutation-negative somatotropinomas (AIPneg), patients with AIPmut somatotropinomas had a younger age at first symptoms (18.9±9.0 vs 26.1±11.7y; p<0.001) and at diagnosis (24.1±10.5 vs 30.1±12.4y; p<0.001), higher rates of pituitary apoplexy (9.5 vs 1.9%; p<0.001), suprasellar extension (66.1 vs 45.3%; p=0.003), extrasellar extension (81.2 vs 68.3%; p=0.032) and a higher mean number of pituitary deficiencies at diagnosis (0.4±0.9 vs 0.2±0.6, p=0.020). The clinical diagnosis of most AIPmut patients was gigantism (55.4 vs 18.4%, p<0.001). The mean final height was higher in the AIPmut somatotropinoma subgroup (187.2±18.4 vs 177.2±19.6cm; p<0.001). AIPmut male patients ended up taller than AIPneg males (193.0±17.7 vs 183.0±23.1cm; p=0.002); similarly, AIPmut female patients were taller than AIPneg ones (175.5±13.0 vs 169.2±8.6cm; p=0.007). Both AIPmut and AIPneg groups had more male patients (60.4% in AIPmut and 52.7% in AIPneg groups). The mean number of overall treatments (2.34±1.65 vs 2.32±1.45; p=0.896) or surgical operations (1.05±0.78 vs 1.07±0.63; p=0.745) did not differ significantly between AIPmut and AIPneg somatotropinomas; however, AIPmut patients were more often treated with radiotherapy (41.7 vs 28.0%; p=0.020). Conclusions:AIPmut somatotropinomas present earlier and more often with pituitary apoplexy, suprasellar and extrasellar extensions, and had a higher number of pituitary deficiencies. The remarkably higher final height in the AIPmut setting, both in males and females, likely reflects the earlier onset of disease, but also emphasizes the management challenges as suggested by the increased proportion of patients requiring radiotherapy.

SAT-464 Management of an Aggressive Growth Hormone Producing Pituitary Macroadenoma

Objective: Acromegaly due to growth hormone (GH) producing pituitary adenoma is a complex disease. Aryl hydrocarbon receptor interacting protein (AIP) mutations cause aggressive pituitary adenomas in young patients. A study showed that AIP gene mutation analysis is positive in 11.7% of patients under 30 years with sporadic pituitary macroadenomas, and in 20% of pediatric patients. We present an aggressive GH producing pituitary adenoma in a young patient where AIP testing might be beneficial. Case presentation: 25 year old male from Ecuador presented to the hospital August 2017 with progressive vision loss over the past 2 months leading to blindness in the right eye. A brain MRI showed a large sellar/suprasellar mass with mass effect on the optic chiasm, measuring 6.7 cm, mild obstructive hydrocephalus. He had normal baseline anterior pituitary hormone work up, and normal diluted prolactin. IGF-1 was not drawn. He underwent partial tumor resection August 2017, but had large residual tumor. Pathology revealed plurihormonal pituitary adenoma.He developed secondary adrenal insufficiency requiring hydrocortisone. He was readmitted November 2017 with headaches, nausea. Head CT revealed obstructive hydrocephalus and enlarging tumor requiring craniotomy/tumor debulking with VP shunt placement. IGF-1 level: 796, with GH of 44. He underwent glucose tolerance test which did not suppress GH. He was started on IM octreotide LAR.He continued to have elevated IGF-1 of 1165, and dose increased to 30 mg Q4 weeks, then further increased to 40 mg Q4 weeks due to IGF-1 of 665. He developed severe insulin resistance, requiring 300 units of insulin per day. He was admitted June 2018 with severe metabolic acidosis in the setting of DKA, and intubated. He underwent a third craniotomy and further tumor debulking due to tumor growth after-which he developed loss of satiety control requiring restraints, causing great difficulty in diabetes control. Discussion: This is an aggressive GH producing pituitary adenoma in a young individual, on high dose octreotide LAR. A multidisciplinary approach to his care is necessary. Further surgical debulking will be necessary in his case. High dose, high frequency octreotide LAR therapy is being considered. AIP (aryl hydrocarbon receptor interacting protein) gene mutation analysis may be beneficial in this case given aggressive nature of his disease and young age. Conclusion: Pituitary adenoma causing acromegaly is a challenging disease.In young individuals, gene mutation analysis may be beneficial in order to optimize clinical genetic investigation and management.

In vivo bioassay to test the pathogenicity of missense human AIP variants

BackgroundHeterozygous germline loss-of-function mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) predispose to childhood-onset pituitary tumours. The pathogenicity of missense variants may pose difficulties for genetic counselling and family...

Germline mutations of aryl hydrocarbon receptor-interacting protein (AIP) gene and somatostatin receptor 1-5 and AIP immunostaining in patients with sporadic acromegaly with poor versus good response to somatostatin analogues.

To determine aryl hydrocarbon interacting protein (AIP) gene variations and AIP and somatostatin receptor (SSTR) 1-5 immunostaining in patients with apparently sporadic acromegaly with poor versus good response to somatostatin analogues (SRLs). A total of 94 patients (66 with poor and 28 with good response to SRLs) were screened for the AIP gene variations using Sanger sequencing. Immunostaining was performed in 60 tumors. Several variations, albeit some with undetermined significance, were detected, especially in poor responder patients. The prevalence of AIP mutation was 2.1% in the whole group and 1.5% in patients with poor response to SRLs. AIP, SSTR2A, and SSTR2B immunostainings were decreased in patients with poor response (p < 0.05 for all), and other SSTRs did not differ between the groups (p > 0.05 for all). Patients with low AIP had decreased levels of SSTR2A and SSTR3 (p < 0.05 for all). AIP and SSTR2A immunostainings were positively correlated to the treatment response and age at diagnosis was negatively correlated (p < 0.05 for all). In poor responder patients with high SSTR2A immunostaining, SSTR2B immunostaining and preoperative tumor size were positively and negatively correlated, respectively, to SRL response (p < 0.05 for all). Lack of response to SRLs does not necessarily increase the risk of harboring AIP mutations. The finding of decreased AIP, SSTR2A, and SSTR2B immunostaining in patients with poor response to SRLs and decreased SSTR2A and SSTR3 level in those with low AIP immunostaining suggests a possible interaction between AIP and some SSTR subtypes that might alter SRL sensitivity.

Study of major genetic factors involved in pituitary tumorigenesis and their impact on clinical and biological characteristics of sporadic somatotropinomas and non-functioning pituitary adenomas.

Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.

AIP and the somatostatin system in pituitary tumours.

Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.

Pure Androgen–Producing Adrenal Tumor: Clinical Features And Pathogenesis

Pure androgen-secreting adrenal tumors (PASATs) are extremely rare, most reports involving only a single case. This study examined 9 cases of PASAT, with an attempt to characterize its clinical features and to explore the pathogenesis. Clinical data of 9 patients with PASAT were retrospectively reviewed. Immunostaining was conducted, and the aryl hydrocarbon receptor-interacting protein gene (AIP) was amplified and directly sequenced. The onset age of the patients ranged from 3.5 to 64 years. All 8 female patients had virilization, whereas the 7-year-old male patient presented with sexual precocity. Serum testosterone levels were elevated (4.1 to 52.3 nmol/L). Adrenal masses were detected and removed in all patients and histologically diagnosed as adrenocortical adenoma or carcinoma. Two patients had both PASATs and growth hormone (GH)-secreting pituitary adenomas (GH pituitary adenoma). Immunohistochemistry revealed nuclear immunoreactivity for p53 in 3 of 7 patients and nuclear immunoreactivity for cyclin D1 in 2 of 7 patients. Immunostaining of β-catenin showed nuclear, cytoplasmic, and membrane immunoreactivity (2 of 7 patients) or merely cytoplasmic immunoreactivity (1 of 7 patients). The adrenocortical carcinoma showed positive staining for both p53 and cyclin D1 and a high Ki-67 index of 60%. Mutations p.Lys177Argfs*19 and p.Asp287Val in the AIP gene were identified in PASATs of the 2 patients with concomitant presence of GH pituitary adenoma. Clinical features of PASATs vary with gender and age of the patients. Abnormal p53 and β-catenin expression might be involved in the tumorigenesis of these tumors. AIP mutations might be responsible for the concomitant presence of PASATs and GH pituitary adenoma. ACA = adrenocortical adenoma ACC = adrenocortical carcinoma AIP = aryl hydrocarbon receptor-interacting protein DHEAS = dehydroepiandrosterone sulfate; GH growth hormone PASAT = pure androgen-secreting adrenal tumor.

Role of Phosphodiesterases on the Function of Aryl Hydrocarbon Receptor-Interacting Protein (AIP) in the Pituitary Gland and on the Evaluation of AIP Gene Variants.

Familial isolated pituitary adenoma (FIPA) is caused in about 20% of cases by loss-of-function germline mutations in the AIP gene. Patients harboring AIP mutations usually present with somatotropinomas resulting either in gigantism or young-onset acromegaly. AIP encodes for a co-chaperone protein endowed with tumor suppressor properties in somatotroph cells. Among other mechanisms proposed to explain this function, a regulatory effect over the 3',5'-cyclic adenosine monophosphate (cAMP) signaling pathway seems to play a prominent role. In this setting, the well-known interaction between AIP and 2 different isoforms of phosphodiesterases (PDEs), PDE2A3 and PDE4A5, is of particular interest. While the interaction with over-expressed AIP does not seem to affect PDE2A3 function, the reported effect on PDE4A5 is, in contrast, reduced enzymatic activity. In this review, we explore the possible implications of these molecular interactions for the function of somatotroph cells. In particular, we discuss how both PDEs and AIP could act as negative regulators of the cAMP pathway in the pituitary, probably both by shared and independent mechanisms. Moreover, we describe how the evaluation of the AIP-PDE4A5 interaction has proven to be a useful tool for testing AIP mutations, complementing other in silico, in vitro, and in vivo analyses. Improved assessment of the pathogenicity of AIP mutations is indeed paramount to provide adequate guidance for genetic counseling and clinical screening in AIP mutation carriers, which can lead to prospective diagnosis of pituitary adenomas.

Aryl Hydrocarbon Receptor-Interacting Protein (AIP) N-Terminus Gene Mutations Identified in Pituitary Adenoma Patients Alter Protein Stability and Function.

Mutations spanning the entire aryl hydrocarbon receptor-interacting protein (AIP) gene have been found in isolated familial cases of pituitary adenomas (PA). Missense mutations located in the N-terminus of the gene have been identified in several patients. However, the functional significance of these mutations remains a matter of controversy. In most studies, the N-terminus of AIP has been shown to regulate protein stability and subcellular localization of the AIP-AHR-HSP90 complex but not to be involved in protein-protein interactions. Other studies found that the N-terminal domain interacts directly with other proteins. The aim of this study was to analyze whether specific N-terminus AIP mutations identified in PA patients would be functionally different from wild-type (WT) AIP. In vitro analyses were used to assess the role of known N-terminus variants, a locally identified mutant, R9Q, and three other commonly genotyped N-terminus mutations R16H, V49M and K103R are found in PA patients. Given the functional effect of WT AIP on cAMP signalling alterations caused by N-terminus mutants on this pathway were also analyzed in GH3 cells. Results indicate that N-terminus mutations lead to de-regulation of the effect of WT AIP on cAMP signalling and increased cAMP thresholds in GH3 cells resulting in increased growth hormone (GH) secretion. Cycloheximide chase analysis identified a variation in protein degradation patterns between WT and N-terminus variants. Therefore, both functional and structural studies reveal that N-terminus mutations in the AIP gene alter protein behaviour significantly and hence can truly be pathogenic in nature.

Feline hypersomatotropism and acromegaly tumorigenesis: a potential role for the AIP gene

Acromegaly in humans is usually sporadic, however up to 20% of familial isolated pituitary adenomas are caused by germline sequence variants of the aryl-hydrocarbon-receptor interacting protein (AIP) gene. Feline acromegaly has similarities to human acromegalic families with AIP mutations. The aim of this study was to sequence the feline AIP gene, identify sequence variants and compare the AIP gene sequence between feline acromegalic and control cats, and in acromegalic siblings. The feline AIP gene was amplified through PCR using whole blood genomic DNA from 10 acromegalic and 10 control cats, and 3 sibling pairs affected by acromegaly. PCR products were sequenced and compared with the published predicted feline AIP gene. A single nonsynonymous SNP was identified in exon 1 (AIP:c.9T > G) of two acromegalic cats and none of the control cats, as well as both members of one sibling pair. The region of this SNP is considered essential for the interaction of the AIP protein with its receptor. This sequence variant has not previously been reported in humans. Two additional synonymous sequence variants were identified (AIP:c.481C > T and AIP:c.826C > T). This is the first molecular study to investigate a potential genetic cause of feline acromegaly and identified a nonsynonymous AIP single nucleotide polymorphism in 20% of the acromegalic cat population evaluated, as well as in one of the sibling pairs evaluated.