Abstract
Context
In sporadic acromegaly, overall AIPmut prevalence is reported as 3, 4.1 and 16 % in studies carried out across Europe. However, it is not known whether the prevalence shows any changes across different ethnicities. The aim of the study was to identify prevalence of AIPmut in a series of Turkish acromegalic patients.
Patients and methods
Direct sequencing of AIP gene was performed in 92 sporadic acromegalic patients.
Results
One patient was found to have a new mutation in exon 6: g67.258,286 (G/A) heterozygote; (GGC/GAC; gly/asp). Apart from this new mutation, previously defined synonymous mutations in AIP gene were detected in seven patients (Exon 4; rs2276020; (GAC/GAT; asp/asp) and six patients were found to have five different intronic mutations in AIP gene which were not previously defined. The patient with pathogenic AIPmut presented at a young age and had an aggressive and treatment resistant tumour. The prevalence of AIPmut in Turkish patients was found to be 1 % in sporadic acromegaly in the present study. In addition, one synonymous mutation which was previously defined and six new intronic mutations have been described in Turkish acromegalic patients. All acromegalic patients with synonymous AIPmut presented with macroadenoma and majority of them had invasive tumour.
Conclusion
The prevalence of AIPmut in Turkish patients was found to be 1 % in sporadic acromegaly in the present study. This ratio increases when younger age groups are taken into account 6 % among patients <30 years of age at the time of diagnosis of acromegaly. The clinical features of acromegaly, such as having large and invasive tumours, may be affected by the presence of synonymous AIPmut.
Similar content being viewed by others
References
Beckers A, Daly AF (2007) The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol 157(4):371–382
Daly AF, Tichomirowa MA, Beckers A (2009) Genetic, molecular and clinical features of familial isolated pituitary adenomas. Horm Res 71(Suppl 2):116–122
Daly AF, Vanbellinghen JF, Khoo SK, Jaffrain-Rea ML, Naves LA, Guitelman MA, Murat A, Emy P, Gimenez-Roqueplo AP, Tamburrano G, Raverot G, Barlier A, De HW, Penfornis A, Ciccarelli E, Estour B, Lecomte P, Gatta B, Chabre O, Sabate MI, Bertagna X, Garcia BN, Stalldecker G, Colao A, Ferolla P, Wemeau JL, Caron P, Sadoul JL, Oneto A, Archambeaud F, Calender A, Sinilnikova O, Montanana CF, Cavagnini F, Hana V, Solano A, Delettieres D, Luccio-Camelo DC, Basso A, Rohmer V, Brue T, Bours V, Teh BT, Beckers A (2007) Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab 92(5):1891–1896
Daly AF, Tichomirowa MA, Petrossians P, Heliovaara E, Jaffrain-Rea ML, Barlier A, Naves LA, Ebeling T, Karhu A, Raappana A, Cazabat L, De ME, Montanana CF, Raverot G, Weil RJ, Sane T, Maiter D, Neggers S, Yaneva M, Tabarin A, Verrua E, Eloranta E, Murat A, Vierimaa O, Salmela PI, Emy P, Toledo RA, Sabate MI, Villa C, Popelier M, Salvatori R, Jennings J, Longas AF, Labarta Aizpun JI, Georgitsi M, Paschke R, Ronchi C, Valimaki M, Saloranta C, De HW, Cozzi R, Guitelman M, Magri F, Lagonigro MS, Halaby G, Corman V, Hagelstein MT, Vanbellinghen JF, Barra GB, Gimenez-Roqueplo AP, Cameron FJ, Borson-Chazot F, Holdaway I, Toledo SP, Stalla GK, Spada A, Zacharieva S, Bertherat J, Brue T, Bours V, Chanson P, Aaltonen LA, Beckers A (2010) Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab 95(11):E373–E383
Korbonits M, Storr H, Kumar AV (2012) Familial pituitary adenomas: who should be tested for AIP mutations? Clin Endocrinol (Oxf) 77(3):351–356
Barlier A, Vanbellinghen JF, Daly AF, Silvy M, Jaffrain-Rea ML, Trouillas J, Tamagno G, Cazabat L, Bours V, Brue T, Enjalbert A, Beckers A (2007) Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas. J Clin Endocrinol Metab 92(5):1952–1955
Cazabat L, Libe R, Perlemoine K, Rene-Corail F, Burnichon N, Gimenez-Roqueplo AP, Dupasquier-Fediaevsky L, Bertagna X, Clauser E, Chanson P, Bertherat J, Raffin-Sanson ML (2007) Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas. Eur J Endocrinol 157(1):1–8
Georgitsi M, Raitila A, Karhu A, Tuppurainen K, Makinen MJ, Vierimaa O, Paschke R, Saeger W, van der Luijt RB, Sane T, Robledo M, De ME, Weil RJ, Wasik A, Zielinski G, Lucewicz O, Lubinski J, Launonen V, Vahteristo P, Aaltonen LA (2007) Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Proc Natl Acad Sci USA 104(10):4101–4105
Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, Castermans E, Villa C, Dimopoulos A, Chittiboina P, Xekouki P, Shah N, Metzger D, Lysy PA, Ferrante E, Strebkova N, Mazerkina N, Zatelli MC, Lodish M, Horvath A, de Alexandre RB, Manning AD, Levy I, Keil MF, Sierra ML, Palmeira L, Coppieters W, Georges M, Naves LA, Jamar M, Bours V, Wu TJ, Choong CS, Bertherat J, Chanson P, Kamenicky P, Farrell WE, Barlier A, Quezado M, Bjelobaba I, Stojilkovic SS, Wess J, Costanzi S, Liu P, Lupski JR, Beckers A, Stratakis CA (2014) Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 371(25):2363–2374
Cazabat L, Bouligand J, Salenave S, Bernier M, Gaillard S, Parker F, Young J, Guiochon-Mantel A, Chanson P (2012) Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients. J Clin Endocrinol Metab 97(4):E663–E670
Occhi G, Trivellin G, Ceccato F, De LP, Giorgi G, Dematte S, Grimaldi F, Castello R, Davi MV, Arnaldi G, Salviati L, Opocher G, Mantero F, Scaroni C (2010) Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia. Eur J Endocrinol 163(3):369–376
Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM, Salmela PI, Paschke R, Gundogdu S, De ME, Makinen MJ, Launonen V, Karhu A, Aaltonen LA (2006) Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312(5777):1228–1230
Colao A, Cappabianca P, Caron P, De ME, Farrall AJ, Gadelha MR, Hmissi A, Rees A, Reincke M, Safari M, T’Sjoen G, Bouterfa H, Cuneo RC (2009) Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomized, open-label, multicentre study. Clin Endocrinol (Oxf) 70(5):757–768
Giustina A, Barkan A, Chanson P, Grossman A, Hoffman A, Ghigo E, Casanueva F, Colao A, Lamberts S, Sheppard M, Melmed S (2008) Guidelines for the treatment of growth hormone excess and growth hormone deficiency in adults. J Endocrinol Investig 31(9):820–838
Melmed S, Colao A, Barkan A, Molitch M, Grossman AB, Kleinberg D, Clemmons D, Chanson P, Laws E, Schlechte J, Vance ML, Ho K, Giustina A (2009) Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 94(5):1509–1517
Rowlands JC, Urban JD, Wikoff DS, Budinsky RA (2011) An evaluation of single nucleotide polymorphisms in the human aryl hydrocarbon receptor-interacting protein (AIP) gene. Drug Metab Pharmacokinet 26(4):431–439
Beckers A, Aaltonen LA, Daly AF, Karhu A (2013) Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev 34(2):239–277
Tichomirowa MA, Barlier A, Daly AF, Jaffrain-Rea ML, Ronchi C, Yaneva M, Urban JD, Petrossians P, Elenkova A, Tabarin A, Desailloud R, Maiter D, Schurmeyer T, Cozzi R, Theodoropoulou M, Sievers C, Bernabeu I, Naves LA, Chabre O, Montanana CF, Hana V, Halaby G, Delemer B, Aizpun JI, Sonnet E, Longas AF, Hagelstein MT, Caron P, Stalla GK, Bours V, Zacharieva S, Spada A, Brue T, Beckers A (2011) High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. Eur J Endocrinol 165(4):509–515
Tuominen I, Heliovaara E, Raitila A, Rautiainen MR, Mehine M, Katainen R, Donner I, Aittomaki V, Lehtonen HJ, Ahlsten M, Kivipelto L, Schalin-Jantti C, Arola J, Hautaniemi S, Karhu A (2015) AIP inactivation leads to pituitary tumorigenesis through defective Galpha-cAMP signaling. Oncogene 34(9):1174–1184
Linnert M, Haupt K, Lin YJ, Kissing S, Paschke AK, Fischer G, Weiwad M, Lucke C (2012) NMR assignments of the FKBP-type PPIase domain of the human aryl-hydrocarbon receptor-interacting protein (AIP). Biomol NMR Assign 6(2):209–212
Ma Q, Whitlock JP Jr (1997) A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Biol Chem 272(14):8878–8884
Martucci F, Trivellin G, Korbonits M (2012) Familial isolated pituitary adenomas: an emerging clinical entity. J Endocrinol Invest 35(11):1003–1014
Chahal HS, Stals K, Unterlander M, Balding DJ, Thomas MG, Kumar AV, Besser GM, Atkinson AB, Morrison PJ, Howlett TA, Levy MJ, Orme SM, Akker SA, Abel RL, Grossman AB, Burger J, Ellard S, Korbonits M (2011) AIP mutation in pituitary adenomas in the 18th century and today. N Engl J Med 364(1):43–50
Oriola J, Lucas T, Halperin I, Mora M, Perales MJ, Alvarez-Escola C, de Paz MN, Diaz SG, Salinas I, Julian MT, Olaizola I, Bernabeu I, Marazuela M, Puig-Domingo M (2013) Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. Eur J Endocrinol 168(1):9–13
Cazabat L, Guillaud-Bataille M, Bertherat J, Raffin-Sanson ML (2009) Mutations of the gene for the aryl hydrocarbon receptor-interacting protein in pituitary adenomas. Horm Res 71(3):132–141
Cazabat L, Bouligand J, Chanson P (2011) AIP mutation in pituitary adenomas. N Engl J Med 364(20):1973–1974
Schofl C, Honegger J, Droste M, Grussendorf M, Finke R, Plockinger U, Berg C, Willenberg HS, Lammert A, Klingmuller D, Jaursch-Hancke C, Tonjes A, Schneidewind S, Flitsch J, Bullmann C, Dimopoulou C, Stalla G, Mayr B, Hoeppner W, Schopohl J (2014) Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study. J Clin Endocrinol Metab 99(12):E2789–E2793. doi:10.1210/jc.2014-2094
Preda V, Korbonits M, Cudlip S, Karavitaki N, Grossman AB (2014) Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort. Eur J Endocrinol 171(5):659–666
Stratakis CA, Tichomirowa MA, Boikos S, Azevedo MF, Lodish M, Martari M, Verma S, Daly AF, Raygada M, Keil MF, Papademetriou J, Drori-Herishanu L, Horvath A, Tsang KM, Nesterova M, Franklin S, Vanbellinghen JF, Bours V, Salvatori R, Beckers A (2010) The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clin Genet 78(5):457–463
Chamary JV, Hurst LD (2005) Evidence for selection on synonymous mutations affecting stability of mRNA secondary structure in mammals. Genome Biol 6(9):R75
Hunt RC, Simhadri VL, Iandoli M, Sauna ZE, Kimchi-Sarfaty C (2014) Exposing synonymous mutations. Trends Genet 30(7):308–321
Igreja S, Chahal HS, King P, Bolger GB, Srirangalingam U, Guasti L, Chapple JP, Trivellin G, Gueorguiev M, Guegan K, Stals K, Khoo B, Kumar AV, Ellard S, Grossman AB, Korbonits M (2010) Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum Mutat 31(8):950–960
Akashi H (2001) Gene expression and molecular evolution. Curr Opin Genet Dev 11(6):660–666
Carlini DB, Chen Y, Stephan W (2001) The relationship between third-codon position nucleotide content, codon bias, mRNA secondary structure and gene expression in the drosophilid alcohol dehydrogenase genes Adh and Adhr. Genetics 159(2):623–633
Chen Y, Carlini DB, Baines JF, Parsch J, Braverman JM, Tanda S, Stephan W (1999) RNA secondary structure and compensatory evolution. Genes Genet Syst 74(6):271–286
Parsch J, Tanda S, Stephan W (1997) Site-directed mutations reveal long-range compensatory interactions in the Adh gene of Drosophila melanogaster. Proc Natl Acad Sci USA 94(3):928–933
Jin Y, Dietz HC, Montgomery RA, Bell WR, McIntosh I, Coller B, Bray PF (1996) Glanzmann thrombasthenia. Cooperation between sequence variants in cis during splice site selection. J Clin Invest 98(8):1745–1754
Liu H, Fu XA, Yu YX, Yu GQ, Yan XX, Liu HX, Tian HQ, Zhang FR (2011) Identification of two novel splice mutations of the ADAR1 gene in two Chinese families with dyschromatosis symmetrica hereditaria. Clin Exp Dermatol 36(7):797–799
Duan J, Antezana MA (2003) Mammalian mutation pressure, synonymous codon choice, and mRNA degradation. J Mol Evol 57(6):694–701
Acknowledgments
This Project was supported by Turkish Council of Scientific and Technological Research. (Project Number: 113S432)
Conflict of interest
The authors have nothing to disclose.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Karaca, Z., Taheri, S., Tanriverdi, F. et al. Prevalence of AIP mutations in a series of Turkish acromegalic patients: are synonymous AIP mutations relevant?. Pituitary 18, 831–837 (2015). https://doi.org/10.1007/s11102-015-0659-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11102-015-0659-0