Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders.

Abstract

Genomic imprinting is an epigenetic phenomenon that leads to parent-specific differential expression of a subset of genes. Most imprinted genes form clusters, or imprinting domains, and are regulated by imprinting control regions. As imprinted genes have an important role in growth and development, aberrant expression of imprinted genes due to genetic or epigenetic abnormalities is involved in the pathogenesis of human disorders, or imprinting disorders. Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder characterized by macrosomia, macroglossia and abdominal wall defects, and exhibits a predisposition to tumorigenesis. The relevant imprinted chromosomal region in BWS is 11p15.5, which consists of two imprinting domains, IGF2/H19 and CDKN1C/KCNQ1OT1. BWS has five known causative epigenetic and genetic alterations: loss of methylation (LOM) at KvDMR1, gain of methylation (GOM) at H19DMR, paternal uniparental disomy, CDKN1C mutations and chromosomal rearrangements. Opposite methylation defects, GOM and LOM, at H19DMR are known to cause clinically opposite disorders: BWS and Silver-Russell syndrome, respectively. Interestingly, a recent study discovered that loss of function or gain of function of CDKN1C also causes clinically opposite disorders, BWS and IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome, respectively. Furthermore, several clinical studies have suggested a relationship between assisted reproductive technology (ART) and the risk of imprinting disorders, along with the existence of trans-acting factors that regulate multiple imprinted differentially methylated regions. In this review, we describe the latest knowledge surrounding the imprinting mechanism of 11p15.5, in addition to epigenetic and genetic etiologies of BWS, associated childhood tumors, the effects of ART and multilocus hypomethylation disorders.

• Authors: Hidenobu Soejima, Ken Higashimoto
• Journal: Journal of human genetics (J Hum Genet) Vol. 58 Issue 7 Pg. 402-9 (Jul 2013) ISSN: 1435-232X [Electronic] England
• PMID: 23719190 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• CDKN1C protein, human
• Cyclin-Dependent Kinase Inhibitor p57

Topics

• Beckwith-Wiedemann Syndrome (genetics)
• Chromosomes, Human, Pair 11 (genetics)
• Cyclin-Dependent Kinase Inhibitor p57 (genetics, metabolism)
• DNA Methylation
• Gene Rearrangement
• Genetic Loci
• Genetic Predisposition to Disease
• Genomic Imprinting
• Humans
• Mutation
• Uniparental Disomy (genetics)