Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.
Bottom Line: Through the analysis of four patients, we identify three novel mutants and determine their effects at the cellular level.Mutations in the Ig-like domain prevent proper disulphide bond formation and are more efficiently targeted to ER-associated degradation.Finally, we show that mutant CMG2 can be rescued in fibroblasts of some patients by treatment with proteasome inhibitors and that CMG2 is then properly transported to the plasma membrane and signalling competent, identifying the ER folding and degradation pathway components as promising drug targets for HFS.
Affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.Show MeSH
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Mentions: Single mutants of the vWA domain cysteines did not drastically affect the migration pattern, i.e. both the precursor and the mature form were observed (Fig 4A), indicating that a significant proportion of the protein was able to exit the ER. Immunofluorescence analysis and surface biotinylation experiments further showed that mutation of Cys-39 or Cys-218 to alanine does not significantly affect targeting of CMG2 to the cell surface (Fig 4B and E).
Affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.