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

Research output: Contribution to journalArticle

113 Citations (Scopus)

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 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
Pages (from-to)950-960
Number of pages11
JournalHuman Mutation
Volume31
Issue number8
DOIs
Publication statusPublished - Aug 2010

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Mutation
Galactosidases
Genes
Two-Hybrid System Techniques
Proteins
Penetrance
Germ-Line Mutation
Sequence Deletion
Phosphoric Diester Hydrolases
Missense Mutation
Cyclic AMP-Dependent Protein Kinases
Luciferases
Computer Simulation
Messenger RNA
Familial Isolated Pituitary Adenoma
aryl hydrocarbon receptor-interacting protein
Silent Mutation
In Vitro Techniques
Genetic Background

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Igreja, S., Chahal, H. S., King, P., Bolger, G. B., Srirangalingam, U., Guasti, L., ... Yoshimoto, K. (2010). Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Human Mutation, 31(8), 950-960. https://doi.org/10.1002/humu.21292

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

In: Human Mutation, Vol. 31, No. 8, 08.2010, p. 950-960.

Research output: Contribution to journalArticle

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, Akker, S, Atkinson, B, Aylwin, S, Baldeweg, S, Bevan, J, Cheetham, T, Chew, S, Choudry, K, Clayton, R, Damjanovic, S, Darzy, K, Dattani, M, Davis, J, Drake, W, Dzeranova, L, Edén, B, Eguchi, K, Fica, S, Flanagan, D, Frohman, L, Gadelha, M, Gallego, P, Gláz, E, Goldman, J, Goldstone, T, Howlett, T, Inder, W, Iwata, T, Kaplan, F, Karavitaki, N, Laws, E, Lechan, R, Levy, M, Matsuno, A, Miljic, D, Modenesi, S, Molitch, M, Musat, M, Orme, S, Patócs, A, Popovic, V, Powell, M, Quinton, R, Randeva, H, Ribeiro De Oliveira, A, Schöfl, C, Soares, B, Spada, A, Strasburger, C, Swords, F, Tsagarakis, S, Vaks, V, Wass, JAH, Widell, H, Yarman, S & Yoshimoto, K 2010, 'Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families', Human Mutation, vol. 31, no. 8, pp. 950-960. https://doi.org/10.1002/humu.21292
Igreja, Susana ; Chahal, Harvinder S. ; King, Peter ; Bolger, Graeme B. ; Srirangalingam, Umasuthan ; Guasti, Leonardo ; Chapple, J. Paul ; Trivellin, Giampaolo ; Gueorguiev, Maria ; Guegan, Katie ; Stals, Karen ; Khoo, Bernard ; Kumar, Ajith V. ; Ellard, Sian ; Grossman, Ashley B. ; Korbonits, Márta ; Akker, Scott ; Atkinson, Brew ; Aylwin, Simon ; Baldeweg, Stephanie ; Bevan, John ; Cheetham, Tim ; Chew, Shern ; Choudry, Kiran ; Clayton, Richard ; Damjanovic, Svetozar ; Darzy, Ken ; Dattani, Mehul ; Davis, Julian ; Drake, Will ; Dzeranova, Larisa ; Edén, Britt ; Eguchi, Kuniki ; Fica, Simona ; Flanagan, Daniel ; Frohman, Lawrence ; Gadelha, Monica ; Gallego, Patricia ; Gláz, Edit ; Goldman, James ; Goldstone, Tony ; Howlett, Trevor ; Inder, Warrick ; Iwata, Takeo ; Kaplan, Felicity ; Karavitaki, Niki ; Laws, Ed ; Lechan, Ron ; Levy, Miles ; Matsuno, Akira ; Miljic, Dragana ; Modenesi, Silvia ; Molitch, Mark ; Musat, Mâdâlina ; Orme, Steve ; Patócs, Attila ; Popovic, Vera ; Powell, Michael ; Quinton, Richard ; Randeva, Harpal ; Ribeiro De Oliveira, Antônio ; Schöfl, Christof ; Soares, Beatriz ; Spada, Anna ; Strasburger, Christian ; Swords, Francesca ; Tsagarakis, Stylianos ; Vaks, Vladimir ; Wass, John A H ; Widell, Hakan ; Yarman, Sema ; Yoshimoto, Katsuhiko. / Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. In: Human Mutation. 2010 ; Vol. 31, No. 8. pp. 950-960.
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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 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.",
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AU - Igreja, Susana

AU - Chahal, Harvinder S.

AU - King, Peter

AU - Bolger, Graeme B.

AU - Srirangalingam, Umasuthan

AU - Guasti, Leonardo

AU - Chapple, J. Paul

AU - Trivellin, Giampaolo

AU - Gueorguiev, Maria

AU - Guegan, Katie

AU - Stals, Karen

AU - Khoo, Bernard

AU - Kumar, Ajith V.

AU - Ellard, Sian

AU - Grossman, Ashley B.

AU - Korbonits, Márta

AU - Akker, Scott

AU - Atkinson, Brew

AU - Aylwin, Simon

AU - Baldeweg, Stephanie

AU - Bevan, John

AU - Cheetham, Tim

AU - Chew, Shern

AU - Choudry, Kiran

AU - Clayton, Richard

AU - Damjanovic, Svetozar

AU - Darzy, Ken

AU - Dattani, Mehul

AU - Davis, Julian

AU - Drake, Will

AU - Dzeranova, Larisa

AU - Edén, Britt

AU - Eguchi, Kuniki

AU - Fica, Simona

AU - Flanagan, Daniel

AU - Frohman, Lawrence

AU - Gadelha, Monica

AU - Gallego, Patricia

AU - Gláz, Edit

AU - Goldman, James

AU - Goldstone, Tony

AU - Howlett, Trevor

AU - Inder, Warrick

AU - Iwata, Takeo

AU - Kaplan, Felicity

AU - Karavitaki, Niki

AU - Laws, Ed

AU - Lechan, Ron

AU - Levy, Miles

AU - Matsuno, Akira

AU - Miljic, Dragana

AU - Modenesi, Silvia

AU - Molitch, Mark

AU - Musat, Mâdâlina

AU - Orme, Steve

AU - Patócs, Attila

AU - Popovic, Vera

AU - Powell, Michael

AU - Quinton, Richard

AU - Randeva, Harpal

AU - Ribeiro De Oliveira, Antônio

AU - Schöfl, Christof

AU - Soares, Beatriz

AU - Spada, Anna

AU - Strasburger, Christian

AU - Swords, Francesca

AU - Tsagarakis, Stylianos

AU - Vaks, Vladimir

AU - Wass, John A H

AU - Widell, Hakan

AU - Yarman, Sema

AU - Yoshimoto, Katsuhiko

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

KW - Acromegaly

KW - AIP

KW - FIPA

KW - Pituitary adenoma

KW - Tumor suppressor

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