Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families

Susana Igreja, Harvinder S. Chahal, Peter King, Graeme B. Bolger, Umasuthan Srirangalingam, Leonardo Guasti, J. Paul Chapple, Giampaolo Trivellin, Maria Gueorguiev, Katie Guegan, Karen Stals, Bernard Khoo, Ajith V. Kumar, Sian Ellard, Ashley B. Grossman, Márta Korbonits*, Scott Akker, Brew Atkinson, Simon Aylwin, Stephanie BaldewegJohn Bevan, Tim Cheetham, Shern Chew, Kiran Choudry, Richard Clayton, Svetozar Damjanovic, Ken Darzy, Mehul Dattani, Julian Davis, Will Drake, Larisa Dzeranova, Britt Edén, Kuniki Eguchi, Simona Fica, Daniel Flanagan, Lawrence Frohman, Monica Gadelha, Patricia Gallego, Edit Gláz, James Goldman, Tony Goldstone, Trevor Howlett, Warrick Inder, Takeo Iwata, Felicity Kaplan, Niki Karavitaki, Ed Laws, Ron Lechan, Miles Levy, Akira Matsuno, Dragana Miljic, Silvia Modenesi, Mark Molitch, Mâdâlina Musat, Steve Orme, Attila Patócs, Vera Popovic, Michael Powell, Richard Quinton, Harpal Randeva, Antônio Ribeiro De Oliveira, Christof Schöfl, Beatriz Soares, Anna Spada, Christian Strasburger, Francesca Swords, Stylianos Tsagarakis, Vladimir Vaks, John A H Wass, Hakan Widell, Sema Yarman, Katsuhiko Yoshimoto

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

148 Scopus citations


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 β-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.

Original languageEnglish (US)
Pages (from-to)950-960
Number of pages11
JournalHuman mutation
Issue number8
StatePublished - Aug 2010


  • AIP
  • Acromegaly
  • FIPA
  • Pituitary adenoma
  • Tumor suppressor

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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