Congenital diseases with defects in DNA methylation maintenance: Focusing on ICF syndrome and multilocus imprinting disturbance.

Abstract

DNA methylation is essential for transcriptional regulation and the maintenance of chromosome stability, and its precise inheritance upon DNA replication is indispensable for cellular homeostasis. The DNMT1/UHRF1 complex is critical in copying DNA methylation with accessory proteins, including CDCA7 and HELLS. The DNMT1/UHRF1 complex is also crucial for maintaining DNA methylation at imprinting control regions during preimplantation development against genome-wide DNA demethylation, an essential process for early embryos to acquire totipotency. Pathogenic variants in the genes involved in the mechanism of DNA methylation maintenance result in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, multilocus imprinting disturbance (MLID), autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCADN), neuropathy, hereditary sensory, type 1E (HSN1E), Kleefstra syndrome 1 (KLEFS1), and immunodeficiency 96 (IMD96). This review discusses recent progress in understanding the possible molecular pathogenesis of these diseases, with a particular focus on recent progress in understanding ICF syndrome and MLID.