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Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.

Deuquet J, Lausch E, Guex N, Abrami L, Salvi S, Lakkaraju A, Ramirez MC, Martignetti JA, Rokicki D, Bonafe L, Superti-Furga A, van der Goot FG - EMBO Mol Med (2011)

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.

View Article: PubMed Central - PubMed

Affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.

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Related in: MedlinePlus

Clinical presentation, pedigrees of HFS families and molecular characterizationAbridged pedigrees of four HFS families are shown, numbers of individuals correspond to Table 1. Symbol notations: squares, males; circles, females; open symbols, unaffected individuals; filled symbols, affected mutation carrier of the nucleotide and predicted amino acid change indicated on top; index patients are marked with a red arrow. Electropherograms of index patients are shown to the right of each pedigree, altered nucleotides are marked in pink in both reference sequence (top) and actual read (bottom); underlined nucleotides indicate deletions or the site of insertions in exon 13. Inserted nucleotides in patients' sequences are also underlined, predicted changes in the amino acid sequence given above. All mutations segregated with the disease phenotype, showing compound homozygosity or homozygosity in patients, heterozygosity in parents, and wild-type alleles or heterozygous mutations in unaffected siblings.
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fig01: Clinical presentation, pedigrees of HFS families and molecular characterizationAbridged pedigrees of four HFS families are shown, numbers of individuals correspond to Table 1. Symbol notations: squares, males; circles, females; open symbols, unaffected individuals; filled symbols, affected mutation carrier of the nucleotide and predicted amino acid change indicated on top; index patients are marked with a red arrow. Electropherograms of index patients are shown to the right of each pedigree, altered nucleotides are marked in pink in both reference sequence (top) and actual read (bottom); underlined nucleotides indicate deletions or the site of insertions in exon 13. Inserted nucleotides in patients' sequences are also underlined, predicted changes in the amino acid sequence given above. All mutations segregated with the disease phenotype, showing compound homozygosity or homozygosity in patients, heterozygosity in parents, and wild-type alleles or heterozygous mutations in unaffected siblings.

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).


Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.

Deuquet J, Lausch E, Guex N, Abrami L, Salvi S, Lakkaraju A, Ramirez MC, Martignetti JA, Rokicki D, Bonafe L, Superti-Furga A, van der Goot FG - EMBO Mol Med (2011)

Clinical presentation, pedigrees of HFS families and molecular characterizationAbridged pedigrees of four HFS families are shown, numbers of individuals correspond to Table 1. Symbol notations: squares, males; circles, females; open symbols, unaffected individuals; filled symbols, affected mutation carrier of the nucleotide and predicted amino acid change indicated on top; index patients are marked with a red arrow. Electropherograms of index patients are shown to the right of each pedigree, altered nucleotides are marked in pink in both reference sequence (top) and actual read (bottom); underlined nucleotides indicate deletions or the site of insertions in exon 13. Inserted nucleotides in patients' sequences are also underlined, predicted changes in the amino acid sequence given above. All mutations segregated with the disease phenotype, showing compound homozygosity or homozygosity in patients, heterozygosity in parents, and wild-type alleles or heterozygous mutations in unaffected siblings.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3377065&req=5

fig01: Clinical presentation, pedigrees of HFS families and molecular characterizationAbridged pedigrees of four HFS families are shown, numbers of individuals correspond to Table 1. Symbol notations: squares, males; circles, females; open symbols, unaffected individuals; filled symbols, affected mutation carrier of the nucleotide and predicted amino acid change indicated on top; index patients are marked with a red arrow. Electropherograms of index patients are shown to the right of each pedigree, altered nucleotides are marked in pink in both reference sequence (top) and actual read (bottom); underlined nucleotides indicate deletions or the site of insertions in exon 13. Inserted nucleotides in patients' sequences are also underlined, predicted changes in the amino acid sequence given above. All mutations segregated with the disease phenotype, showing compound homozygosity or homozygosity in patients, heterozygosity in parents, and wild-type alleles or heterozygous mutations in unaffected siblings.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.

Show MeSH
Related in: MedlinePlus