Human Genetics

, Volume 104, Issue 3, pp 205–210

Functional analysis of the p57KIP2 gene mutation in Beckwith-Wiedemann syndrome

Authors

  • Zahurul A. Bhuiyan
    • Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
  • Hitomi Yatsuki
    • Department of Biochemistry, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: mukait@post.saga-med.ac.jp, Tel.: +81-952-34-2260, Fax: +81-952-34-2067
  • Toshiyuki Sasaguri
    • Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
  • Keiichiro Joh
    • Department of Biochemistry, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: mukait@post.saga-med.ac.jp, Tel.: +81-952-34-2260, Fax: +81-952-34-2067
  • Hidenobu Soejima
    • Department of Biochemistry, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: mukait@post.saga-med.ac.jp, Tel.: +81-952-34-2260, Fax: +81-952-34-2067
  • Xike Zhu
    • Department of Biochemistry, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: mukait@post.saga-med.ac.jp, Tel.: +81-952-34-2260, Fax: +81-952-34-2067
  • Izuho Hatada
    • Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
  • Hiroko Morisaki
    • Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
  • Takayuki Morisaki
    • Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
  • Tsunehiro Mukai
    • Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan
Original investigation

DOI: 10.1007/s004390050937

Cite this article as:
Bhuiyan, Z., Yatsuki, H., Sasaguri, T. et al. Hum Genet (1999) 104: 205. doi:10.1007/s004390050937

Abstract

p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin/cyclin-dependent kinase (Cdk) complexes, and is a negative regulator of cell proliferation. The gene encoding p57KIP2 is located at 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome (BWS). Previously we demonstrated that p57KIP2 is imprinted and only the maternal allele is expressed in both mice and humans. We also showed mutations found in p57KIP2 in patients with BWS that were transmitted from the patients’ carrier mothers, indicating that the expressed maternal allele was mutant and that the repressed paternal allele was normal. In the study reported here, we performed functional analysis of the two mutated p57KIP2 genes. We showed that the nonsense mutation found in the Cdk inhibitory domain in a BWS patient rendered the protein inactive with consequent complete loss of its role as a cell cycle inhibitor and of its nuclear localization. We also showed that the mutation in the QT domain, although completely retaining its cell cycle regulatory activity, lacked nuclear localization and was thus prevented from performing its role as an active cell cycle inhibitor. Consequently, no active p57KIP2 would have existed, which might have caused the disorders in BWS patients.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1999