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
Related in: MedlinePlus
Mentions: Upon expression of C39F or C218R CMG2, both the mature and the ER precursor forms were observed under reducing conditions (Fig 6A), but the relative abundance of the precursor was higher than for the WT protein, as even more apparent after EndoH treatment (Fig 6B). Partial ER retention was confirmed by immunofluorescence analysis, where we could detect both plasma membrane and ER staining, as particularly indicated by the staining of the nuclear membrane (illustrated for C39F in Fig 6C).
Affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.