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Human Molecular Genetics, 2000, Vol. 9, No. 3 453-460
© 2000 Oxford University Press

The cell cycle control gene ZAC/PLAGL1 is imprinted—a strong candidate gene for transient neonatal diabetes

Mamoru Kamiya1,2, Hannah Judson3, Yasushi Okazaki1, Moriaki Kusakabe1, Masami Muramatsu1, Shuji Takada1,4, Nobuo Takagi4, Takahiro Arima1,5, Norio Wake5, Katsunori Kamimura6, Kenichi Satomura7, Robert Hermann8, David T. Bonthron3 and Yoshihide Hayashizaki1,2,+

1CREST, Japan Science and Technology Corporation (JST), Genome Exploration Research Group, Genomic Sciences Center (GSC), Genome Science Laboratory and Biogenetic Research Center, Riken Tsukuba Life Science Center, the Institute of Physical and Chemical Research (RIKEN), Ibaraki 305-0074, Japan, 2Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki 305-0006, Japan, 3Molecular Medicine Unit, University of Leeds, Leeds LS9 7TF, UK, 4Graduate School of Environmental Earth Science, Hokkaido University, Hokkaido 060-0808, Japan, 5Department of Reproductive Physiology and Endocrinology, Medical Institute of Bioregulation, Kyushu University, Oita 874-0838, Japan, 6Department of Pediatrics, Kobe City General Hospital, Kobe 650-0046, Japan, 7Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan, 8Department of Pediatrics, University Medical School of Pécs, Pécs 7623, Hungary

We describe a screen for new imprinted human genes, and the identification in this way of ZAC (zinc finger protein which regulates apoptosis and cell cycle arrest)/PLAGL1 (pleomorphic adenoma of the salivary gland gene like 1) as a strong candidate gene for transient neonatal diabetes mellitus (TNDM). To screen for imprinted genes, we compared parthenogenetic DNA from the chimeric patient FD and androgenetic DNA from hydatidiform mole, using restriction landmark genome scanning for methylation. This resulted in identification of two novel imprinted loci, one of which (NV149) we mapped to the TNDM region of 6q24. From analysis of the corresponding genomic region, it was determined that NV149 lies ~60 kb upstream of the ZAC/PLAGL1 gene. RT–PCR analysis was used to confirm that this ZAC/PLAGL1 is expressed only from the paternal allele in a variety of tissues. TNDM is known to result from upregulation of a paternally expressed gene on chromosome 6q24. The paternal expression, map position and known biological properties of ZAC/PLAGL1 make it highly likely that it is the TNDM gene. In particular, ZAC/PLAGL1 is a transcriptional regulator of the type 1 receptor for pituitary adenylate cyclase-activating polypeptide, which is the most potent known insulin secretagog and an important mediator of autocrine control of insulin secretion in the pancreatic islet.

+ To whom correspondence should be addressed. Tel: +81 298 36 9145; Fax: +81 298 36 9098; Email: yosihide@rtc.riken.go.jp


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