Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith–Wiedemann syndrome and Wilms' tumor

Abstract

We have analyzed several cases of Beckwith-Wiedemann syndrome (BWS) with Wilms' tumor in a familial setting, which give insight into the complex controls of imprinting and gene expression in the chromosome 11p15 region. We describe a 2.2-kbp microdeletion in the H19͞insulin-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. Maternal inheritance of the deletion is associated with IGF2 loss of imprinting and up-regulation of IGF2 mRNA. However, in at least one affected family member a second genetic lesion (a duplication of maternal 11p15) was identified and accompanied by a further increase in IGF2 mRNA levels 35-fold higher than control values. Our results suggest that the combined effects of the H19͞IGF2-imprinting center microdeletion and 11p15 chromosome duplication were necessary for manifestation of BWS.insulin-like growth factor 2 ͉ H19 ͉ differentially methylated region

Epigenetic deregulation of imprinting in congenital diseases of aberrant growth

“…For instance, there are rare micro-deletions at the human H19 ICR that lead to loss of IGF2 imprinting and, hence, BWS. (50,51) One of these small deletions comprised only two of the six CTCF-binding sites at this ICR. Nevertheless, this, somehow, induced hypermethylation along the entire ICR upon maternal transmission, leading to biallelic IGF2 expression and loss of H19 expression.…”

IGF2: Epigenetic regulation and role in development and disease

“…Most of these mutations affect imprinting; quite often, biallelic IGF2 expression and H19 methylation are observed (reviewed in [16]). BWS usually occurs sporadically, but in rare familial cases IGF2 LOI may be caused by deletions of the CTCF binding sites in the maternal IGF2/H19 ICR [59,60].…”

Beckwith–Wiedemann syndrome

“…33 Gain-of-methylation defects occur at IC1 (5%); some of these methylation alterations have been associated with genomic alterations. [34][35][36] Methylation changes that occur in conjunction with genomic alterations are important because of their heritability. Epigenetic alterations that involve both IC1 and IC2 generally indicate paternal UPD (20% of cases) for a chromosomal segment including 11p15.5.…”

“…This is associated with mutations in CDKN1C or microdeletions of IC1 and very rarely IC2. 32,33,[35][36][37]40,44,45 Omphalocele. This is associated with an IC2 defect or CDKN1C mutation.…”