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 inAIPaccount only for 15–25% of FIPA families.CDKN1Bmutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations inCDKN1Boccur among a large cohort ofAIPmutation-negative FIPA kindreds. Eighty-eightAIPmutation-negative FIPA families were studied and 124 affected subjects underwent sequencing ofCDKN1B. Functional analysis of putativeCDKN1Bmutations was performed usingin silicoandin vitroapproaches. GermlineCDKN1Banalysis 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. p27I119Tshows an abnormal migration pattern by SDS–PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic becauseIn vitroeffects were not seen. In conclusion, two patients had germline sequence changes inCDKN1B, which led to functional alterations in the encoded p27 proteinsin vitro. Such rareCDKN1Bvariants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients makeCDKN1Bsequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role ofCDKN1Bin pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.