Arima T, Drewell R A, Arney K L, Inoue J, Makita Y, Hata A, Oshimura M, Wake N, Surani M A
Wellcome/CRC Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK.
Hum Mol Genet. 2001 Jul 1;10(14):1475-83. doi: 10.1093/hmg/10.14.1475.
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 approximately 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.
短暂性新生儿糖尿病（TNDM）与宫内生长迟缓、脱水及胰岛素缺乏有关。一些TNDM患者表现出6号染色体q24区域的父源单亲二倍体（UPD），目前已鉴定出该区域至少有两个印记基因，即HYMAI和ZAC。在此我们表明，在小鼠同线性位点上与mZac1和mHymai部分重叠的差异甲基化CpG岛可能是大约120 - 200 kb区域的印记控制区域（ICR）。该区域在精子中未甲基化，但在卵母细胞中可能甲基化，这种差异在植入前和植入后发育过程中亲代等位基因之间持续存在。我们还表明，在这个ICR内，存在一个在小鼠和人类之间具有高度同源性的区域。使用报告基因表达分析，我们证明这个保守区域在甲基化时作为一个强大的转录抑制因子起作用。最后，我们提供体内证据表明，在大多数核型正常的TNDM患者中，高度同源区域内存在甲基化缺失。我们提出这个ICR调节该区域内印记基因的表达；该区域的表观遗传或基因突变可能导致TNDM，可能是通过影响胰腺和/或垂体中ZAC的表达。
