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

Takahiro Arima, Robert A. Drewell, Katharine L. Arney, Jun Inoue, Yoshio Makita, Akira Hata, Mitsuo Oshimura, Norio Wake, M. Azim Surani

研究成果: Article査読

84 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1475-1483
ページ数9
ジャーナルHuman molecular genetics
10
14
DOI
出版ステータスPublished - 2001 7月 1
外部発表はい

ASJC Scopus subject areas

  • 分子生物学
  • 遺伝学
  • 遺伝学(臨床)

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