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: In the least affected families 1 and 2, different compound heterozygous mutations of cmg2 were detected (Table 2). Patient 1 carries a c.116G>T transversion predicted to cause a novel p.C39F amino acid substitution in the amino terminus of CMG2. In the second allele, a previously described (Hanks et al, 2003) c.1074delT single nucleotide deletion in exon 13 was found, which modifies the open reading frame by a frame shift leading to a change in the cytosolic tail of the protein and a premature stop (Fig 1). Patient 2 carries a missense mutation resulting in a c.928G>T transversion, leading to substitution of valine 310 in the ectodomain with a phenylalanine (Fig. 1). In the second allele, a single base insertion (c.1073_1074insC) was found again in exon 13, also leading to a frame shift and a premature stop. Both cases of severe HFS in families 3 and 4 proved to be associated with homozygous mutations. Patient 3 carried a biallelic novel c.945T>G transversion, leading to the change of cysteine 315 to tryptophan (Fig 1). Patient 4 is homozygous for the same c.1073_1074insC insertion detected in Patient 2 (Fig 1). The presence of insertions or deletions in exon 13 for three out of the four patients supports the previous observation that a GC-rich stretch in exon 13 is a mutational hot spot (Dowling et al, 2003; El-Kamah et al, 2010; Hanks et al, 2003; Lee et al, 2005).
Affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.