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Nature 423, 91-96 (1 May 2003) | doi:10.1038/nature01535; Received 31 December 2002; Accepted 17 February 2003

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An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene

Shinji Hirotsune1,2, Noriyuki Yoshida1, Amy Chen3, Lisa Garrett3, Fumihiro Sugiyama4, Satoru Takahashi4, Ken-ichi Yagami4, Anthony Wynshaw-Boris3,5 & Atsushi Yoshiki6

  1. Division of Neuroscience, Research Center for Genomic Medicine, Saitama Medical School Yamane 1397-1, Hidaka City, Saitama 350-1241, Japan
  2. PRESTO, Japan Science and Technology Corporation, Hon-cho 4-1-8, Kawaguchi, Saitama, Japan
  3. Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bldg 49, Room 4C80 49, Convent Drive, Bethesda, Maryland 20892, USA
  4. Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
  5. Departments of Pediatrics and Medicine, UCSD Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Drive, Mailstop 0627, La Jolla, California 92093-0627, USA
  6. Experimental Animal Division, Department of Biological Systems, BioResource Center, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan

Correspondence to: Shinji Hirotsune1,2 Correspondence and requests for materials should be addressed to S.H. (Email: shinjih@saitama-med.ac.jp).

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A pseudogene is a gene copy that does not produce a functional, full-length protein1. The human genome is estimated to contain up to 20,000 pseudogenes2, 3. Although much effort has been devoted to understanding the function of pseudogenes, their biological roles remain largely unknown. Here we report the role of an expressed pseudogene—regulation of messenger-RNA stability—in a transgene-insertion mouse mutant exhibiting polycystic kidneys and bone deformity. The transgene was integrated into the vicinity of the expressing pseudogene of Makorin1, called Makorin1-p1. This insertion reduced transcription of Makorin1-p1, resulting in destabilization of Makorin1 mRNA in trans by way of a cis-acting RNA decay element within the 5' region of Makorin1 that is homologous between Makorin1 and Makorin1-p1. Either Makorin1 or Makorin1-p1 transgenes could rescue these phenotypes. Our findings demonstrate a specific regulatory role of an expressed pseudogene, and point to the functional significance of non-coding RNAs.

  1. Division of Neuroscience, Research Center for Genomic Medicine, Saitama Medical School Yamane 1397-1, Hidaka City, Saitama 350-1241, Japan
  2. PRESTO, Japan Science and Technology Corporation, Hon-cho 4-1-8, Kawaguchi, Saitama, Japan
  3. Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bldg 49, Room 4C80 49, Convent Drive, Bethesda, Maryland 20892, USA
  4. Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
  5. Departments of Pediatrics and Medicine, UCSD Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Drive, Mailstop 0627, La Jolla, California 92093-0627, USA
  6. Experimental Animal Division, Department of Biological Systems, BioResource Center, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan

Correspondence to: Shinji Hirotsune1,2 Correspondence and requests for materials should be addressed to S.H. (Email: shinjih@saitama-med.ac.jp).