Given that H814 of DNMT3B is involved in both aromatic stacking interactions (H814–H814′) and hydrogen bonding (H814–D817′) in the RD interface, it is perhaps not surprising that we found the H814R mutation to most seriously disrupt DNMT3B dimer assembly and MTase activity among the four mutants we tested, and that it leads to multiple syndromes, including not only the classical ICF phenotypes, such as the absence of IgA and IgG, respiratory infections, branching of chromosomes 1, 9, and 16, but also severe psychomotor retardation (Wijmenga et al., 2000). Here, DNMT3B is linked to respiratory tract infectious disorder.