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Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans

Natalia S Pellegata1, Leticia Quintanilla-Martinez, Heide Siggelkow

  • 1Institutes of Pathology, GSF-National Research Center for Environment and Health, 85764 Neuherberg, Germany. natalia.pellegata@gsf.de

Proceedings of the National Academy of Sciences of the United States of America
|October 13, 2006
PubMed

Insights

Multiple endocrine neoplasia-like syndrome (MENX) in rats is caused by a Cdkn1b mutation, leading to reduced p27(Kip1). A similar mutation in human CDKN1B predisposes to endocrine tumors, linking p27(Kip1) to multiple endocrine neoplasia.

Area of Science:

  • Endocrinology
  • Genetics
  • Oncology

Background:

  • Multiple endocrine neoplasia (MEN) syndromes involve tumors in endocrine glands.
  • MENX in rats shares tumor characteristics with human MEN types 1 and 2.
  • Previous mapping excluded known MEN-associated genes.

Purpose of the Study:

  • To fine-map the MenX locus in rats.
  • To identify the genetic cause of MENX.
  • To investigate the role of p27(Kip1) in endocrine tumorigenesis.

Main Methods:

  • Fine genetic mapping of the MenX locus on rat chromosome 4.
  • Mutation analysis of the Cdkn1b gene in affected rats.
  • Germline mutation screening of the human CDKN1B gene in MEN1-negative patients.

Main Results:

  • A homozygous frameshift mutation in rat Cdkn1b was identified in MENX rats, causing a p27(Kip1) protein reduction.
  • A germline nonsense mutation in human CDKN1B was found in a MEN1-negative patient with pituitary and parathyroid tumors.
  • Pedigree analysis confirmed the association of the human CDKN1B mutation with an MEN1-like phenotype.

Conclusions:

  • Germline mutations in p27(Kip1) are implicated in the development of multiple endocrine tumors.
  • Cdkn1b mutations can cause MENX in rats and contribute to MEN1-like syndromes in humans.
  • p27(Kip1) is a key factor in endocrine tumor predisposition.

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