Immunodeficiency, Centromere Instability and Facial Anomalies (ICF) Syndrome

  • Schematic structure of the ZBTB24 protein, which is mutated in ICF Syndrome patients.

  • Image showing depletion of DNMT3B (siRNA) or a known constitutive centromere protein (CENP-C) that interacts with DNMT3B. This causes genome instability in the form of an increase of anaphase bridges at mitosis, which is indicated by the red arrows at the left and quantitated in the graph at the right.

A number of 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 methylated DNA). Another disease, immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is caused by mutations in DNMT3B, ZBTB24 and possibly other yet to be identified genes. ICF 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.

Study of ICF syndrome patients provides a system in which the functions of DNMT3B 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 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, which is not a DNA methyltransferase but a zinc finger DNA binding protein, is being further examined for how it controls genomic DNA methylation patterns. As mutations in ZBTB24 were only recently discovered, much remains unknown about its role in regulating the epigenome.

Although mutations in the DNMTs are rare in human disease, mutations in other epigenetic control genes are common. As such, researchers 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 also yield new treatments for ICF syndrome or diseases with defects in regulating genomic methylation patterns.