title: Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds.
abstract: Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.
authors.affiliation: Department of Endocrinology, Centre Hospitalier Universitaire de Liège, Domaine Universitaire du Sart-Tilman, University of Liège, 4000 Liège, Belgium.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Tichomirowa
authors.forename: Misu
authors.initials: M
authors.lastname: Lee
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Daly
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marinoni
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Jaffrain-Rea
authors.forename: Luciana A
authors.initials: LA
authors.lastname: Naves
authors.forename: Patrice
authors.initials: P
authors.lastname: Rodien
authors.forename: Vincent
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authors.lastname: Rohmer
authors.forename: Fabio Rueda
authors.initials: FR
authors.lastname: Faucz
authors.forename: Philippe
authors.initials: P
authors.lastname: Caron
authors.forename: Bruno
authors.initials: B
authors.lastname: Estour
authors.forename: Pierre
authors.initials: P
authors.lastname: Lecomte
authors.forename: Françoise
authors.initials: F
authors.lastname: Borson-Chazot
authors.forename: Alfred
authors.initials: A
authors.lastname: Penfornis
authors.forename: Maria
authors.initials: M
authors.lastname: Yaneva
authors.forename: Mirtha
authors.initials: M
authors.lastname: Guitelman
authors.forename: Emily
authors.initials: E
authors.lastname: Castermans
authors.forename: Catherine
authors.initials: C
authors.lastname: Verhaege
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Wémeau
authors.forename: Antoine
authors.initials: A
authors.lastname: Tabarin
authors.forename: Carmen
authors.initials: C
authors.lastname: Fajardo Montañana
authors.forename: Brigitte
authors.initials: B
authors.lastname: Delemer
authors.forename: Veronique
authors.initials: V
authors.lastname: Kerlan
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Sadoul
authors.forename: Christine
authors.initials: C
authors.lastname: Cortet Rudelli
authors.forename: Françoise
authors.initials: F
authors.lastname: Archambeaud
authors.forename: Sabine
authors.initials: S
authors.lastname: Zacharieva
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
authors.forename: Thierry
authors.initials: T
authors.lastname: Brue
authors.forename: Alain
authors.initials: A
authors.lastname: Enjalbert
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Pellegata
authors.forename: Albert
authors.initials: A
authors.lastname: Beckers
mesh_terms: D000236:Adenoma / Q000235:genetics*; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005190:Family; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics*
chemical_list: C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D050760:Cyclin-Dependent Kinase Inhibitor p27