DNA methylation is an essential epigenetic mechanism in the regulation of gene expression. Specific enzymes, DNA methyltransferases, add methyl groups to certain nucleotides of the DNA and may thus, for example, repress transcription of genes. One of these DNA methyltransferases is encoded by the DNMT3A gene. Researchers have now discovered de novo mutations in this gene that increase the function of the DNMT3A protein and cause microcephalic dwarfism, a group of monogenic disorders characterized by pre- and postnatal extreme and proportionate growth failure. Resulting from an origin during early development, it is associated with microcephaly and a reduced brain volume, which distinguishes it from other forms of growth reduction. DNMT3A mutations affecting protein function have previously been described to cause a contrasting phenotype, an overgrowth syndrome called Tatton Rahman Brown syndrome.

The researchers performed extensive functional experiments on patient cells, mouse embryonic stem cells and a CRISPR/Cas9-generated mouse model in their study and conclude that the newly identified mutations in DNMT3A impair binding of the PWWP domain of the protein to specific histone modifications (H3K36me2 and H3K36me3), thus altering DNA methylation in patient cells. They also assume that an interplay exists between DNA methylation and epigenetic regulation by polycomb group proteins at genomic regions essential for correct development.

The results of this study have been published in Nature Genetics.