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

Authors
  • Santos, Ruda de Luna Almeida1
  • Crovella, Sergio2
  • Celsi, Fulvio3
  • 1 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
  • 2 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. , (Italy)
  • 3 Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria 65/1, 34137 Trieste, Italy. Electronic address: [email protected] , (Italy)
Type
Published Article
Journal
Gene
Publication Date
Mar 15, 2015
Volume
559
Issue
1
Pages
99–101
Identifiers
DOI: 10.1016/j.gene.2015.01.029
PMID: 25620160
Source
Medline
Keywords
License
Unknown

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.

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