Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) Syndrome: A Disease of DNA Methylation
Several human genetic diseases are linked to mutations in genes that regulate the epigenome (for example, Rett syndrome is caused by mutations in a gene that binds to, or reads, methylated DNA, called MeCP2). Another disease — immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome — is caused by mutations in DNMT3B, ZBTB24, CDCA7, HELLS and possibly other yet to be identified genes. ICF syndrome is a rare disorder characterized by immune defects (primarily B cell development), facial anomalies and profound genomic instability involving the centromeric regions of chromosomes 1, 9 and 16.
The use of ICF syndrome patient-derived cells provides a system in which the functions of DNMT3B and other ICF genes can be studied. The goal of this project is to better understand DNA methylation defects in this disorder and develop a model to study methylation-targeting mechanisms.
Research includes characterizing ICF DNMT3B and ZBTB24 mutations for functional consequence and relating these effects to disease phenotype, probing how these mutations impact local and global gene expression and chromatin structure, and examining how DNMT3B and ZBTB24 influence genomic stability and recombination. ZBTB24 (a zinc finger DNA binding protein, rather than a DNA methyltransferase) is being further examined for how it controls genomic DNA methylation patterns.
Mutations in the DNMTs have been identified in human genetic diseases and cancer. As such, researchers in the Epigenetic Etiology of Human Disease Laboratory expect that studying ICF syndrome will generate novel information on the role of DNA methylation in general in health and disease states. In addition, these studies may yield new treatments for ICF syndrome or diseases with defects in regulating genomic methylation patterns.