Tomoharu Tokutomi
   Department   Kawasaki Medical School  Kawasaki Medical School, Department of Pediatrics,
   Position   Professor with Special Assignment
Article types 原著
Language English
Peer review Peer reviewed
Title Hypomethylation of a centromeric block of ICR1 is sufficient to cause Silver-Russell syndrome.
Journal Formal name：Journal of medical genetics
ISSN code：0022-2593/1468-6244
Domestic / ForeginForegin
Publisher BMJ
Volume, Issue, Page 58(6),pp.422-425
Author and coauthor Ken Higashimoto,Hijiri Watanabe,Yuka Tanoue,Hidefumi Tonoki,Tomoharu Tokutomi,Satoshi Hara,Hitomi Yatsuki,Hidenobu Soejima
Publication date 2021/06
Summary Silver-Russell syndrome (SRS) is a representative imprinting disorder. A major cause is the loss of methylation (LOM) of imprinting control region 1 (ICR1) within the <italic>IGF2/H19</italic> domain. ICR1 is a gametic differentially methylated region (DMR) consisting of two repeat blocks, with each block including three CTCF target sites (CTSs). ICR1-LOM on the paternal allele allows CTCF to bind to CTSs, resulting in <italic>IGF2</italic> repression on the paternal allele and biallelic expression of <italic>H19</italic>. We analysed 10 differentially methylated sites (DMSs) (ie, seven CTSs and three somatic DMRs within the <italic>IGF2/H19</italic> domain, including two <italic>IGF2</italic>-DMRs and the <italic>H19</italic>-promoter) in five SRS patients with ICR1-LOM. Four patients showed consistent hypomethylation at all DMSs; however, one exhibited a peculiar LOM pattern, showing LOM at the centromeric region of the <italic>IGF2</italic>/<italic>H19</italic> domain but normal methylation at the telomeric region. This raised important points: there may be a separate regulation of DNA methylation for the two repeat blocks within ICR1; there is independent control of somatic DMRs under each repeat block; sufficient <italic>IGF2</italic> repression to cause SRS phenotypes occurs by LOM only in the centromeric block; and the need for simultaneous methylation analysis of several DMSs in both blocks for a correct molecular diagnosis.
DOI 10.1136/jmedgenet-2020-106907
PMID 32447322
PermalinkURL https://syndication.highwire.org/content/doi/10.1136/jmedgenet-2020-106907