Similarly to what is proposed for maternally inherited BWS mutations and CTCF and OCT4/SOX2 binding, we suggest that deletions of the <i>H19/IGF2</i>:IG-DMR result in SRS with LOM if ZFP57 binding on the paternal chromosome is affected.
Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-β pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.
Not only ICR1 microdeletions involving the CTCF-binding site, but also point mutations and a small deletion of the OCT-binding site have been shown to trigger methylation defects in BWS.
Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission.
In patient-derived cell lines, the mat/pat asymmetric distribution of these epigenetic marks was lost with H3K9me3 and H4K20me3 becoming biallelic in the BWS and H3K4me2, H3K27me3 and H3K9ac together with CTCF-cohesin becoming biallelic in the SRS.
Using bisulfite treatment and a real-time PCR-based methylation assay (QAMA), we analyzed the third and sixth CTCF-binding sites (CTS3, CTS6) in 5 patients with CTS3 hypomethylation, in 14 patients who were suspected to have SRS but were normal by Southern blot analysis, and in 1 patient with body asymmetry without any other features of SRS or Beckwith-Wiedemann syndrome (BWS).
We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor.