ArticleHuman molecular genetics2013
The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF-binding sites.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 87 citations in OpenAlex.
- Methylation profile characteristics in the H19/IGF2:IG-DMR revealed by long-read sequencing analysis in patients with Beckwith-Wiedemann syndrome having defects in the OCT4/SOX2 binding site.Clinical epigenetics · 2026Article
- Thirteen cases support the clinical significance of imprinting center 1 (IC1) microdeletions in Beckwith-Wiedemann syndrome.Clinical epigenetics · 2025Article
- Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith-Wiedemann syndrome-like overgrowth.Communications biology · 2024Article
- Deletion ofInternational journal of molecular sciences · 2022Article
- 3D or Not 3D: Shaping the Genome during Development.Cold Spring Harbor perspectives in biology · 2022Review
- Ongoing Challenges in the Diagnosis of 11p15.5-Associated Imprinting Disorders.Molecular diagnosis & therapy · 2022Article
- Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences.Clinical epigenetics · 2022Article
- Whole-genome methylation analysis of testicular germ cells from cryptozoospermic men points to recurrent and functionally relevant DNA methylation changes.Clinical epigenetics · 2021Article
- The number of the CTCF binding sites of the H19/IGF2:IG-DMR correlates with DNA methylation and expression imprinting in a humanized mouse model.Human molecular genetics · 2021Article
- Review
- Case Report: A Novel Deletion in the 11p15 Region Causing a Familial Beckwith-Wiedemann Syndrome.Frontiers in genetics · 2021Article
- Modeling human epigenetic disorders in mice: Beckwith-Wiedemann syndrome and Silver-Russell syndrome.Disease models & mechanisms · 2020Review
- Maternal Microdeletion at theEpigenetics insights · 2020Article
- High-resolution analysis of germ cells from men with sex chromosomal aneuploidies reveals normal transcriptome but impaired imprinting.Clinical epigenetics · 2019Article
- Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management.International journal of molecular sciences · 2019Review
- One protein to rule them all: The role of CCCTC-binding factor in shaping human genome in health and disease.Seminars in cell & developmental biology · 2019Review
- Genomic imprinting disorders: lessons on how genome, epigenome and environment interact.Nature reviews. Genetics · 2019Review
- Novel familial distal imprinting centre 1 (11p15.5) deletion provides further insights in imprinting regulation.Clinical epigenetics · 2019Article
- Intergenerational response to the endocrine disruptor vinclozolin is influenced by maternal genotype and crossing scheme.Reproductive toxicology (Elmsford, N.Y.) · 2018Article
- Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.Nature reviews. Endocrinology · 2018Review
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Authors and funding
17 authors at 9 institutions in 2 countries.
Funding
Abstract
At chromosome 11p15.5, the imprinting centre 1 (IC1) controls the parent of origin-specific expression of the IGF2 and H19 genes. The 5 kb IC1 region contains multiple target sites (CTS) for the zinc-finger protein CTCF, whose binding on the maternal chromosome prevents the activation of IGF2 and allows that of H19 by common enhancers. CTCF binding helps maintaining the maternal IC1 methylation-free, whereas on the paternal chromosome gamete-inherited DNA methylation inhibits CTCF interaction and enhancer-blocking activity resulting in IGF2 activation and H19 silencing. Maternally inherited 1.4-2.2 kb deletions are associated with methylation of the residual CTSs and Beckwith-Wiedemann syndrome, although with different penetrance and expressivity. We explored the relationship between IC1 microdeletions and phenotype by analysing a number of previously described and novel mutant alleles. We used a highly quantitative assay based on next generation sequencing to measure DNA methylation in affected families and analysed enhancer-blocking activity and CTCF binding in cultured cells. We demonstrate that the microdeletions mostly affect IC1 function and CTCF binding by changing CTS spacing. Thus, the extent of IC1 inactivation and the clinical phenotype are influenced by the arrangement of the residual CTSs. A CTS spacing similar to the wild-type allele results in moderate IC1 inactivation and is associated with stochastic DNA methylation of the maternal IC1 and incomplete penetrance. Microdeletions with different CTS spacing display severe IC1 inactivation and are associated with IC1 hypermethylation and complete penetrance. Careful characterization of the IC1 microdeletions is therefore needed to predict recurrence risks and phenotypical outcomes.
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