DNA (cytosine-5-)-methyltransferase 1 (DNMT1) is the maintenance enzyme that catalyzes the transfer of methyl groups from S-adenosyl methionine to the C5 position of cytosine residues in DNA.  DNA methylation is at the heart of epigenetic imprinting and is involved in the regulation of gene expression.  Aberrant methylation is seen in several disease states including cancer, overgrowth disorders, hereditary sensory and autonomic neuropathy type IE, and other neurological disorders.  Three patients with the overgrowth disorder Beckwith Wiedemann syndrome, and loss of methylation at a critical imprinting centre on chromosome region 11p15.5 within the KCNQ1OT1 locus, were ascertained as carrying missense mutations within DNMT1. The resulting amino acid substitutions; R136C, H1118R and R1223H were either extremely rare or novel substitutions, not previously characterized.  The crystal structure of a DNMT1 fragment was used to model the location of the residues.  Two of the residues were in the solved structure and affected surface residues outside of the catalytic domain.  A third residue (R136C) was not part of the DNMT1 crystal structure but was near a crystallographically solved SET7/9 - DNMT1 peptide structure.  Literature searches show that the R136C and H1118R mutations are near hotspots of post-translational modifications that control the stability of DNMT-1 through methylation, demethylation, acetylation, deacetylation and phosphorylation switches.  Crystal structures of DNMT1, SET7/9 –DNMT1 peptide, AKT, lysine-specific demethylase and acetyltransferases were used as starting points to model the effect of mutations on the interactions of DNMT1 with each of these critical enzymes.  These models provide an explanation for clinical pathology at the cellular and molecular level.