Oppositely imprinted genes p57Kip2 and Igf2 interact in a mouse model for Beckwith–Wiedemann syndrome

  1. Tamara Caspary,
  2. Michele A. Cleary,
  3. Elizabeth J. Perlman,
  4. Pumin Zhang,
  5. Stephen J. Elledge, and
  6. Shirley M. Tilghman
  1. Howard Hughes Medical Institute and Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544 USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205 USA; Division of Basic Sciences, National Jewish Medical and Research Center, Department of Pharmacology and Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80206 USA; Departments of Biochemistry and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 USA

Abstract

Beckwith–Wiedemann syndrome (BWS) is a clinically variable disorder characterized by somatic overgrowth, macroglossia, abdominal wall defects, visceromegaly, and an increased susceptibility to childhood tumors. The disease has been linked to a large cluster of imprinted genes at human chromosome 11p15.5. A subset of BWS patients has been identified with loss-of-function mutations inp57KIP2 , a maternally expressed gene encoding a G1 cyclin-dependent kinase inhibitor. Some patients display loss of imprinting of IGF2, a fetal-specific growth factor that is paternally expressed. To understand how the same disease can result from misregulation of two linked, but unrelated, genes, we generated a mouse model for BWS that both harbors a null mutation inp57Kip2 and displays loss of Igf2 imprinting. These mice display many of the characteristics of BWS, including placentomegaly and dysplasia, kidney dysplasia, macroglossia, cleft palate, omphalocele, and polydactyly. Some, but not all, of the phenotypes are shown to be Igf2 dependent. In two affected tissues, the two imprinted genes appear to act in an antagonistic manner, a finding that may help explain how BWS can arise from mutations in either gene.

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Footnotes

  • Corresponding author.

  • E-MAIL stilghman{at}molbio.princeton.edu; FAX (609) 258-3345.

    • Received August 23, 1999.
    • Accepted October 15, 1999.
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