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EGFR mutations cause a lethal syndrome of epithelial dysfunction with progeroid features.

Ganetzky R, Finn E, Bagchi A, Zollo O, Conlin L, Deardorff M, Harr M, Simpson MA, McGrath JA, Zackai E, Lemmon MA, Sondheimer N - Mol Genet Genomic Med (2015)

Bottom Line: The children were born prematurely, had abnormalities in skin and hair, suffered multisystem organ failure, and died in the neonatal period from intestinal perforation.EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed.The heterologously expressed extracellular domain was impaired in stability and the binding of EGF.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania ; Division of Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.

ABSTRACT
The epidermal growth factor receptor (EGFR) is part of a large family of receptors required for communicating extracellular signals through internal tyrosine kinases. Epidermal growth factor (EGF) signaling is required for tissue development, whereas constitutive activation of this signaling pathway is associated with oncogenic transformation. We identified homozygous c.1283G>A (p.Gly428Asp) mutations in the extracellular domain of EGFR in two siblings. The children were born prematurely, had abnormalities in skin and hair, suffered multisystem organ failure, and died in the neonatal period from intestinal perforation. EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF. Cells from the affected patient undergo early senescence with accelerated expression of β-galactosidase and shortened telomeres at all passages when compared to controls. A comparison of homozygous inherited regions from a separate report of a patient from the same ethnic background and EGFR genotype confirms the pathogenicity of EGFR mutations in congenital disease.

No MeSH data available.


Related in: MedlinePlus

Binding of wild-type and G428D sEGFR to immobilized EGF, assessed using surface plasmon resonance (SPR). Equilibrium responses relative to a blank surface are plotted as a function of injected receptor concentration.
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fig04: Binding of wild-type and G428D sEGFR to immobilized EGF, assessed using surface plasmon resonance (SPR). Equilibrium responses relative to a blank surface are plotted as a function of injected receptor concentration.

Mentions: To evaluate the effect of the EGFR:c.1283G>A (p.Gly428Asp) mutation on the ability of EGFR to bind its ligands, we generated purified recombinant EGFR extracellular region (sEGFR) as described and used surface plasmon resonance to measure ligand binding as described (Ferguson et al. 2000). During purification of the c.1283G>A (p.Gly428Asp)-mutated sEGFR variant (sEGFRGly428Asp), it was found to run as a broad peak in size exclusion chromatography, indicating a degree of misfolding and aggregation. The resulting purified sEGFRG428D protein bound EGF approximately 100-fold more weakly than wild-type sEGFR (Fig.4). These data suggest that the EGFR:c.1283G>A (p.Gly428Asp) mutation causes EGFR’s extracellular region to fold incorrectly, consistent with both reduced levels of the protein in patient-derived cells (and efforts to express EGFRGly428Asp exogenously) and loss of EGF binding. Glycine 428 is on one of the ligand-binding domains in EGFR (domain III), but is distant from the ligand-binding site. Its substitution with an aspartate would project that acidic residue into the hydrophobic core of domain III, likely resulting in impaired folding and/or stability.


EGFR mutations cause a lethal syndrome of epithelial dysfunction with progeroid features.

Ganetzky R, Finn E, Bagchi A, Zollo O, Conlin L, Deardorff M, Harr M, Simpson MA, McGrath JA, Zackai E, Lemmon MA, Sondheimer N - Mol Genet Genomic Med (2015)

Binding of wild-type and G428D sEGFR to immobilized EGF, assessed using surface plasmon resonance (SPR). Equilibrium responses relative to a blank surface are plotted as a function of injected receptor concentration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585453&req=5

fig04: Binding of wild-type and G428D sEGFR to immobilized EGF, assessed using surface plasmon resonance (SPR). Equilibrium responses relative to a blank surface are plotted as a function of injected receptor concentration.
Mentions: To evaluate the effect of the EGFR:c.1283G>A (p.Gly428Asp) mutation on the ability of EGFR to bind its ligands, we generated purified recombinant EGFR extracellular region (sEGFR) as described and used surface plasmon resonance to measure ligand binding as described (Ferguson et al. 2000). During purification of the c.1283G>A (p.Gly428Asp)-mutated sEGFR variant (sEGFRGly428Asp), it was found to run as a broad peak in size exclusion chromatography, indicating a degree of misfolding and aggregation. The resulting purified sEGFRG428D protein bound EGF approximately 100-fold more weakly than wild-type sEGFR (Fig.4). These data suggest that the EGFR:c.1283G>A (p.Gly428Asp) mutation causes EGFR’s extracellular region to fold incorrectly, consistent with both reduced levels of the protein in patient-derived cells (and efforts to express EGFRGly428Asp exogenously) and loss of EGF binding. Glycine 428 is on one of the ligand-binding domains in EGFR (domain III), but is distant from the ligand-binding site. Its substitution with an aspartate would project that acidic residue into the hydrophobic core of domain III, likely resulting in impaired folding and/or stability.

Bottom Line: The children were born prematurely, had abnormalities in skin and hair, suffered multisystem organ failure, and died in the neonatal period from intestinal perforation.EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed.The heterologously expressed extracellular domain was impaired in stability and the binding of EGF.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania ; Division of Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.

ABSTRACT
The epidermal growth factor receptor (EGFR) is part of a large family of receptors required for communicating extracellular signals through internal tyrosine kinases. Epidermal growth factor (EGF) signaling is required for tissue development, whereas constitutive activation of this signaling pathway is associated with oncogenic transformation. We identified homozygous c.1283G>A (p.Gly428Asp) mutations in the extracellular domain of EGFR in two siblings. The children were born prematurely, had abnormalities in skin and hair, suffered multisystem organ failure, and died in the neonatal period from intestinal perforation. EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF. Cells from the affected patient undergo early senescence with accelerated expression of β-galactosidase and shortened telomeres at all passages when compared to controls. A comparison of homozygous inherited regions from a separate report of a patient from the same ethnic background and EGFR genotype confirms the pathogenicity of EGFR mutations in congenital disease.

No MeSH data available.


Related in: MedlinePlus