title: Comment to Santos et al., "hyper-IgD and periodic fever syndrome: a new MVK mutation (p.R277G) associated with a severe phenotype".
abstract: 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=0 kcal/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.
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Ruda de Luna Almeida
authors.initials: Rde L
authors.lastname: Santos
authors.affiliation: Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127 Trieste, Italy; Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65/1, 34137 Trieste, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Crovella
authors.affiliation: Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65/1, 34137 Trieste, Italy. Electronic address: fulvio.celsi@gmail.com.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Celsi
mesh_terms: D005334:Fever / Q000235:genetics*; D006801:Humans; D007072:Immunoglobulin D / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*
chemical_list: D007072:Immunoglobulin D; D017853:Phosphotransferases (Alcohol Group Acceptor)
keywords: HIDS; Immune system; Mevalonate Kinase; Mevalonate Kinase Deficiency; Mevalonic aciduria; Molecular modeling; Periodic fevers