Comment to Santos et al., “Hyper-IgD and periodic fever syndrome: A new MVK mutation (p.R277G) associated with a severe phenotype”

We performed molecular modeling analysis onto a novel mutation in the gene MVK, described by Santos et al., found to be causative of a severe form of Hyper-IgD/Mevalonate Kinase Deficiency. The mutation p.R277G, in our analysis, lowers the binding affinity for some enzyme's substrates. Interestingly, we found that p.R277G mutation inhibits binding of Isopentenyl Pyrophosphate (IPP) (binding free energy=0kcal/mol), one of isoprenoids responsible for feedback-inhibition of MVK. IPP is known to be an activator of a specific class of T-cells and we can hypothesize that increased levels of this metabolite generate an aberrant immune system response. Indeed other experiments are needed to verify this hypothesis; however, this work demonstrates usefulness of molecular modeling in generating novel pathogenic hypothesis. •Mutated Mevalonate Kinase (MVK) R277G has a similar tridimensional structure as the WT protein.•In MVK R277G the binding site for ATP and its substrate, the Mevalonate has lower affinity for its ligands.•In MVK R277G the feedback inhibitor Isopentenyl Pyrophosphate (IPP) does not bind to the protein.•Increased IPP, due to feedback inhibition failure, could lead to immunitary system activation.