Tatton-Brown-Rahman Syndrome
In 2 unrelated patients with Tatton-Brown-Rahman syndrome (TBRS; 615879), Shen et al. (2017) identified a de novo heterozygous c.2645G-A transition (c.2645G-A, NM_175629.2) in the DNMT3A gene, resulting in an R882H substitution.
In a 6-year-old girl with TBRS, Kosaki et al. (2017) identified heterozygosity for the de novo R882H mutation in the DNMT3A gene.
Acute Myeloid Leukemia, Somatic
Of 62 patients with acute myelogenous leukemia (AML; 601626) who were found to have a somatic mutation in the DNMT3A gene, Ley et al. (2010) found that 27 had a C-to-T transition at a CpG dinucleotide, resulting in an arg882-to-his (R882H) substitution.
Functional Studies of DNMT3A R882H
Using size-exclusion chromatography, Nguyen et al. (2019) confirmed that human DNMT3A formed large oligomeric species, as well as smaller complexes around the size of a tetramer, with large oligomers having lower methyltransferase activity relative to smaller complexes. The dominant-negative DNMT3A R882H mutant stabilized DNMT3A oligomer formation and shifted the DNMT3A oligomer equilibrium toward higher-order multimers, resulting in a dose-dependent reduction of enzyme activity compared with wildtype DNMT3A. In contrast, mutations that disrupted the oligomer-forming interface of the DNMT3A catalytic domain caused a significant shift from large oligomers to smaller species, with reduced enzymatic activity relative to wildtype and comparable with that of R882H. DNMT3L (606588) disrupted formation of large oligomers to activate wildtype DNMT3A by binding to and breaking down higher-order DNMT3A into smaller, more active complexes. Likewise, DNMT3L bound to the R882H mutant, but activity of the R882H mutant was only partially restored relative to wildtype DNMT3A, suggesting that R882H interferes with DNMT3A methyltransferase activity by an additional mechanism. Further analysis revealed that the R882H mutation also compromised the DNA-binding ability of DNMT3A.
Sandoval and Reich (2019) found that wildtype DNMT3A and the DNMT3A R882H mutant were differentially responsive to modulation by p53 (TP53; 191170), as p53 failed to inhibit methylation activity of DNMT3A R882H.
Using purified recombinant proteins, Norvil et al. (2020) showed that DNMT3A R882 mutants lost the cooperative kinetic mechanism in methylation of DNA substrates compared with wildtype DNMT3A. R882 played a key role in the interaction of DNMT3A with DNA, and the R882H mutation altered the specificity of DNMT3A such that it adopted a substrate preference similar to that of DNMT3B (602900), making DNMT3A R882H a DNMT3B-like enzyme. The authors noted that DNMT3A and DNMT3B redundantly methylate many genomic regions in cells, but they also have preferred and specific targets, as Dnmt3a preferentially methylates major satellite repeats in pericentric regions in mouse cells, whereas Dnmt3b preferentially methylates minor satellite repeats in centromeric regions. Analysis with mouse embryonic stem cells revealed that mouse Dnmt3a R878H mutant retained activity for minor satellite DNA and methylated Dnmt3b-preferred target sites but lost its preference for sites methylated by Dnmt3a.
