Human Molecular Genetics, 2001, Vol. 10, No. 14 1475-1483
© 2001 Oxford University Press
A conserved imprinting control region at the HYMAI/ZAC domain is implicated in transient neonatal diabetes mellitus
Wellcome/CRC Institute of Cancer and Developmental Biology, and Physiological Laboratory, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK, 1Department of Molecular and Cell Genetics, School of Life Sciences, Faculty of Medicine, Tottori University, Nishimachi 86, Yonago, Tottori 683-8503, Japan, 2Department of Public Health, Asahikawa Medical College, Midorigaoka-Higashi 2111, Asahikawa, Hokkaido, 078-8510, Japan and 3Department of Reproductive Physiology and Endocrinology, Medical Institute of Bioregulation, Kyusyu University, 4546 Tsurumihara, Beppu, Oita 874-0838, Japan
Transient neonatal diabetes mellitus (TNDM) is associated with intra-uterine growth retardation, dehydration and a lack of insulin. Some TNDM patients exhibit paternal uniparental disomy (UPD) of chromosome 6q24, where at least two imprinted genes, HYMAI and ZAC, have so far been characterized. Here we show that the differentially methylated CpG island that partially overlaps mZac1 and mHymai at the syntenic mouse locus is a likely imprinting control region (ICR) for the 
120–200 kb domain. The region is unmethylated in sperm but probably methylated in oocytes, a difference that persists between parental alleles throughout pre- and post-implantation development. We also show that within this ICR, there is a region that exhibits a high degree of homology between mouse and human. Using a reporter expression assay, we demonstrate that this conserved region acts as a strong transcriptional repressor when methylated. Finally, we provide in vivo evidence that in the majority of TNDM patients with a normal karyotype, there is a loss of methylation within the highly homologous region. We propose that this ICR regulates expression of imprinted genes within the domain; epigenetic or genetic mutations of this region probably result in TNDM, possibly by affecting expression of ZAC in the pancreas and/or the pituitary.
+ To whom correspondence should be addressed. Tel: +44 1223 334136; Fax: +44 1223 334089; Email: as10021@mole.bio.cam.ac.ukPresent address:Robert A. Drewell, 401 Barker Hall #3204, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
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