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Germ-line mutations in p27 Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans

2006; National Academy of Sciences; Volume: 103; Issue: 42 Linguagem: Inglês

10.1073/pnas.0603877103

1091-6490

Natalia S. Pellegata, Leticia Quintanilla‐Martinez, Heide Siggelkow, Elenore Samson, Karin Bink, Heinz Höfler, Falko Fend, Jochen Graw, Michael J. Atkinson,

Hedgehog Signaling Pathway Studies

MENX is a recessive multiple endocrine neoplasia-like syndrome in the rat. The tumor spectrum in MENX overlaps those of human multiple endocrine neoplasia (MEN) types 1 and 2. We mapped the MenX locus to the distal part of rat chromosome 4, excluding the homologs of the genes responsible for the MEN syndromes ( RET and MEN1 ) and syndromes with an endocrine tumor component ( VHL and NF1 ). We report the fine mapping of the disease locus and the identification of a homozygous frameshift mutation in Cdkn1b , encoding the cyclin-dependent kinase inhibitor p27 Kip1 . As a consequence of the mutation, MENX-affected rats show dramatic reduction in p27 Kip1 protein. We have identified a germ-line nonsense mutation in the human CDKN1B gene in a MEN1 mutation-negative patient presenting with pituitary and parathyroid tumors. Expanded pedigree analysis shows that the mutation is associated with the development of an MEN1-like phenotype in multiple generations. Our findings demonstrate that germ-line mutations in p27 Kip1 can predispose to the development of multiple endocrine tumors in both rats and humans.