Germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations in patients with apparently sporadic pituitary macroadenomas (PMA): initial results

Abstract Context: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. Objective: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). Design: This was a multicenter, international, collaborative study. Setting: The study was conducted in 34 university endocrinology and genetics departments in nine countries. Patients: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. Main Outcome Measures: Presence/absence and description of AIP gene mutations were the main outcome measures. Intervention: There was no intervention. Results: 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 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. Conclusions: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

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Acromegalic cardiomyopathy in pituitary-specific aryl hydrocarbon receptor interacting protein (Aip) gene knockout animals

Endocrine Abstracts ◽

10.1530/endoabs.77.oc1.3 ◽

2021 ◽

Author(s):

Anisha Mistry ◽

Gregory Funge ◽

Sonia Sebastian ◽

Qadeer Aziz ◽

Antonia Solomou ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Gene Knockout ◽

Interacting Protein ◽

Aryl Hydrocarbon ◽

Acromegalic Cardiomyopathy ◽

Aip Gene ◽

Knockout Animals

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Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers

British Journal of Cancer ◽

10.1038/sj.bjc.6603573 ◽

2007 ◽

Vol 96 (2) ◽

pp. 352-356 ◽

Cited By ~ 39

Author(s):

M Georgitsi ◽

A Karhu ◽

R Winqvist ◽

T Visakorpi ◽

K Waltering ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Mutation Analysis ◽

Interacting Protein ◽

Aryl Hydrocarbon ◽

Prostate Cancers ◽

Aip Gene

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Frequency of AIP Gene Mutations in Young Patients With Acromegaly: A Registry-Based Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-2094 ◽

2014 ◽

Vol 99 (12) ◽

pp. E2789-E2793 ◽

Cited By ~ 19

Author(s):

Christof Schöfl ◽

Jürgen Honegger ◽

Michael Droste ◽

Martin Grussendorf ◽

Reinhard Finke ◽

...

Keyword(s):

Family History ◽

Direct Sequencing ◽

Positive Family History ◽

Young Patients ◽

Gene Mutations ◽

Interacting Protein ◽

Aryl Hydrocarbon ◽

Number Of Patients ◽

The Individual ◽

Aip Gene

Context: Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. Objective: The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. Design: The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. Intervention: DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. Results: Five patients had either a mutation (c.490C>T, c.844C>T, and c.911G>A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. Conclusions: The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.

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An Evaluation of Single Nucleotide Polymorphisms in the Human Aryl Hydrocarbon Receptor-Interacting Protein (AIP) Gene

Drug Metabolism and Pharmacokinetics ◽

10.2133/dmpk.dmpk-11-sc-013 ◽

2011 ◽

Vol 26 (4) ◽

pp. 431-439 ◽

Cited By ~ 12

Author(s):

J. Craig Rowlands ◽

Jonathan D. Urban ◽

Daniele Staskal Wikoff ◽

Robert A. Budinsky

Keyword(s):

Single Nucleotide Polymorphisms ◽

Aryl Hydrocarbon Receptor ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Interacting Protein ◽

Aryl Hydrocarbon ◽

Aip Gene

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Aryl hydrocarbon receptor interacting protein(AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas

Clinical Endocrinology ◽

10.1111/j.1365-2265.2008.03266.x ◽

2008 ◽

Vol 69 (4) ◽

pp. 621-627 ◽

Cited By ~ 52

Author(s):

Marianthi Georgitsi ◽

Ernesto De Menis ◽

Salvatore Cannavò ◽

Markus J. Mäkinen ◽

Karoliina Tuppurainen ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Children And Adolescents ◽

Gene Mutation ◽

Mutation Analysis ◽

Pituitary Adenomas ◽

Interacting Protein ◽

Aryl Hydrocarbon ◽

Aip Gene ◽

Gene Mutation Analysis

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Familial acromegaly due to aryl hydrocarbon receptor-interacting protein (AIP) gene mutation in a Turkish cohort

Pituitary ◽

10.1007/s11102-013-0493-1 ◽

2013 ◽

Vol 17 (3) ◽

pp. 220-226 ◽

Cited By ~ 7

Author(s):

Mutlu Niyazoglu ◽

Muge Sayitoglu ◽

Sinem Firtina ◽

Esra Hatipoglu ◽

Nurperi Gazioglu ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Gene Mutation ◽

Interacting Protein ◽

Aryl Hydrocarbon ◽

Aip Gene

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High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas

Acta Endocrinologica ◽

10.1530/eje-11-0304 ◽

2011 ◽

Vol 165 (4) ◽

pp. 509-515 ◽

Cited By ~ 102

Author(s):

Maria A Tichomirowa ◽

Anne Barlier ◽

Adrian F Daly ◽

Marie-Lise Jaffrain-Rea ◽

Cristina Ronchi ◽

...

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Pediatric Patients ◽

Young Patients ◽

Gene Mutations ◽

Clinical Analysis ◽

Clinical Genetic ◽

Interacting Protein ◽

Aip Gene ◽

Pituitary Macroadenomas

BackgroundAryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments.MethodsWe included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age.ResultsOverall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas.ConclusionGermline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

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Familial isolated pituitary adenoma syndrome

Orvosi Hetilap ◽

10.1556/oh.2011.29093 ◽

2011 ◽

Vol 152 (18) ◽

pp. 722-730 ◽

Cited By ~ 1

Author(s):

Judit Dénes ◽

Márta Korbonits ◽

Erika Hubina ◽

Gábor László Kovács ◽

László Kovács ◽

...

Keyword(s):

Pituitary Adenoma ◽

Aryl Hydrocarbon Receptor ◽

Pituitary Adenomas ◽

Protein Gene ◽

Gene Mutations ◽

Carney Complex ◽

Incomplete Penetrance ◽

Causative Gene ◽

Interacting Protein ◽

Aryl Hydrocarbon

Familial pituitary adenomas occur in multiple endocrine neoplasia type 1, Carney complex, as well as in familial isolated pituitary adenoma syndrome. Familial isolated pituitary adenoma syndrome is an autosomal dominant disease with incomplete penetrance. Pituitary adenomas occur in familial setting but without any other specific tumors. In 20-40% of families with this syndrome, mutations have been identified in the aryl hydrocarbon receptor interacting protein gene while in the rest of the families the causative gene or genes have not been identified. Families carrying aryl hydrocarbon receptor interacting protein gene mutations have a distinct phenotype with younger age at diagnosis and a predominance of somatotroph and lactotroph adenomas. Germline mutations of the aryl hydrocarbon receptor interacting protein gene can be occasionally identified in usually young-onset seemingly sporadic cases. Genetic and clinical testing of relatives of patients with aryl hydrocarbon receptor interacting protein gene mutations can lead to earlier diagnosis and treatment at an earlier stage of the pituitary tumor. Orv. Hetil., 2011, 152, 722–730.

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