A conserved imprinting control region at the HYMAI/ZAC domain is implicated in transient neonatal diabetes mellitus

Transient neonatal diabetes mellitus (TNDM) is associated with intra-uterin e growth retardation, dehydration and a lack of insulin. Some TNDM patients exhibit paternal uniparental disomy (UPD) of chromosome 6q24, where at lea st two imprinted genes, HYMAI and ZAC, have so far been characterized. Here we show that the differentially methylated CpG island that partially overl aps mZac1 and mHymai at the syntenic mouse locus is a likely imprinting con trol region (ICR) for the similar to 120-200 kb domain. The region is unmet hylated in sperm but probably methylated in oocytes, a difference that pers ists between parental alleles throughout pre- and post-implantation develop ment. 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 expressio n assay, we demonstrate that this conserved region acts as a strong transcr iptional repressor when methylated. Finally, we provide in vivo evidence th at in the majority of TNDM patients with a normal karyotype, there is a los s of methylation within the highly homologous region. We propose that this ICR regulates expression of imprinted genes within the domain; epigenetic o r genetic mutations of this region probably result in TNDM, possibly by aff ecting expression of ZAC in the pancreas and/or the pituitary.