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

Susana C Igreja (1) , Harvey S Chahal (1) , Peter J King (1) , Graeme B Bolger (2) , Umasuthan Srirangalingam (1) , Leonardo Guasti (1) , Paul J Chapple (1) , Giampaolo Trivellin (1) , Maria Gueorguiev (1) , Katie Guegan (3) , Karen Stals (3) , Bernard Khoo (4) , Ajith V Kumar (1) , Sian Ellard (3) , Ashley B Grossman (1) , Marta Korbonits (1)

1 Endocrinology
2 O'Neal Comprehensive Cancer Center, University of Alabama
3 Department of Molecular Genetics, Royal Devon and Exeter Foundation Trust
4 Department of Endocrinology

FFamilial isolated pituitary adenoma (FIPA) is an autosomal dominant condition with variable genetic background and incomplete penetrance. Germline mutations of the aryl hydrocarbon-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±11.2yr) than AIP mutation-negative patients (40.4±14.5yr). 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.

Mots clés: Life Sciences

Susana C Igreja, Harvey S Chahal, Peter J King, Graeme B Bolger, Umasuthan Srirangalingam, et al.. Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Human Mutation, 2010, 31 (8), pp.950. ⟨10.1002/humu.21292⟩. ⟨hal-00552399⟩