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Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype.

AbstractOBJECTIVE:
The aim of this study was to investigate the presence of germline mutations in the CDKN1B gene that encodes the cyclin-dependent kinase (Cdk) inhibitor p27 in multiple endocrine neoplasia 1 (MEN1)-like Spanish index patients. The CDKN1B gene has recently been identified as a tumor susceptibility gene for MEN4, with six germline mutations reported so far in patients with a MEN-like phenotype but negative for MEN1 mutations.
DESIGN AND METHODS:
Fifteen Spanish index cases with MEN-like symptoms were screened for mutations in the CDKN1B gene and the mutant variant was studied functionally by transcription/translation assays in vitro and in transiently transfected HeLa cells.
RESULTS:
We report the identification of a heterozygous GAGA deletion in the 5'-UTR of CDKN1B, NM_004064.3:c.-32_-29del, in a patient affected by gastric carcinoid tumor and hyperparathyroidism. This deletion falls inside the region that is responsible for CDKN1B transcription and is predicted to destroy a secondary stem and loop structure that includes the GAGAGA element responsible for ribosome recruitment. Accordingly, in vitro studies of coupled transcription/translation assays and transient transfection in HeLa cells showed that the GAGA deletion in the CDKN1B 5'-UTR significantly impairs the transcription of downstream reporter luciferase (of ∼40-60%) and, possibly, the translation of the corresponding mRNA. This mutation was associated with a significant reduction in the amount of CDKN1B mRNA in peripheral blood leukocytes from the patient, as demonstrated by quantitative real-time PCR.
CONCLUSIONS:
Our results confirm that germline CDKN1B mutations may predispose to a human MEN4 condition and add novel evidence that alteration in the transcription/translation rate of CDKN1B mRNA might be the mechanism implicated in tumor susceptibility.
AuthorsDonatella Malanga, Silvia De Gisi, Miriam Riccardi, Marianna Scrima, Carmela De Marco, Mercedes Robledo, Giuseppe Viglietto
JournalEuropean journal of endocrinology (Eur J Endocrinol) Vol. 166 Issue 3 Pg. 551-60 (Mar 2012) ISSN: 1479-683X [Electronic] England
PMID22129891 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CDKN1B protein, human
  • Cyclin-Dependent Kinase Inhibitor p27
Topics
  • Adult
  • Aged
  • Base Sequence
  • Cyclin-Dependent Kinase Inhibitor p27 (genetics)
  • Female
  • Germ-Line Mutation (genetics)
  • HeLa Cells
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Multiple Endocrine Neoplasia Type 1 (diagnosis, genetics)
  • Phenotype
  • Spain

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