title: Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families.
abstract: 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 beta-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.
authors.affiliation: Department of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom EC1M 6BQ.
authors.forename: Susana
authors.initials: S
authors.lastname: Igreja
authors.forename: Harvinder S
authors.initials: HS
authors.lastname: Chahal
authors.forename: Peter
authors.initials: P
authors.lastname: King
authors.forename: Graeme B
authors.initials: GB
authors.lastname: Bolger
authors.forename: Umasuthan
authors.initials: U
authors.lastname: Srirangalingam
authors.forename: Leonardo
authors.initials: L
authors.lastname: Guasti
authors.forename: J Paul
authors.initials: JP
authors.lastname: Chapple
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Trivellin
authors.forename: Maria
authors.initials: M
authors.lastname: Gueorguiev
authors.forename: Katie
authors.initials: K
authors.lastname: Guegan
authors.forename: Karen
authors.initials: K
authors.lastname: Stals
authors.forename: Bernard
authors.initials: B
authors.lastname: Khoo
authors.forename: Ajith V
authors.initials: AV
authors.lastname: Kumar
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005190:Family; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010911:Pituitary Neoplasms / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; C103265:aryl hydrocarbon receptor-interacting protein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases