The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome

DNA methylation is an important regulator of genetic information in species ranging from bacteria to humans. DNA methylation appears to be critical fo r mammalian development because mice nullizygous for a targeted disruption of the DNMT1 DNA methyltransferase die at an early embryonic stage. No DNA methyltransferase mutations have been reported in humans until now. We desc ribe here the first example of naturally occurring mutations in a mammalian DNA methyltransferase gene. These mutations occur in patients with a rare autosomal recessive disorder, which is termed the ICF syndrome, for immunod eficiency, centromeric instability, and facial anomalies. Centromeric insta bility of chromosomes 1, 9, and 16 is associated with abnormal hypomethylat ion of CpG sites in their pericentromeric satellite regions. We are able to complement this hypomethylation defect by somatic cell fusion to Chinese h amster ovary cells, suggesting that the ICF gene is conserved in the hamste r and promotes de novo methylation. ICF has been localized to a 9-centimorg an region of chromosome 20 by homozygosity mapping. By searching for homolo gies to known DNA methyltransferases, we identified a genomic sequence in t he ICF region that contains the homologue of the mouse Dnmt3b methyltransfe rase gene. Using the human sequence to screen ICF kindreds, we, discovered mutations in four patients from three families. Mutations include two misse nse substitutions and a 3-aa insertion resulting from the creation of a nov el 3' splice acceptor. None of the mutations were found in over 200 normal chromosomes. We conclude that mutations in the DNMT3B are responsible for t he ICF syndrome.