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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

Increased senescence is associated with the G428D mutation as evidenced by decreased replicative capacity over serial passages (A), increased telomere shortening over serial passages (B), and increased beta-galactosidase staining (C).
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fig05: Increased senescence is associated with the G428D mutation as evidenced by decreased replicative capacity over serial passages (A), increased telomere shortening over serial passages (B), and increased beta-galactosidase staining (C).

Mentions: EGF was immobilized by amine coupling to an activated CM5 surface as previously described (Ferguson et al. 2000; PMID 10970856). sEGFRWT and sEGFRG428D proteins were flowed over this surface as well as a control surface at a flow rate of 10 μL/min for 10 min, which was sufficient to reach equilibrium even at low receptor concentrations. The relative responses shown in Figure5 were fit to Langmuir single-site binding isotherms in Prism 6.0 (Graphpad, La Jolla, CA, USA).


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)

Increased senescence is associated with the G428D mutation as evidenced by decreased replicative capacity over serial passages (A), increased telomere shortening over serial passages (B), and increased beta-galactosidase staining (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Increased senescence is associated with the G428D mutation as evidenced by decreased replicative capacity over serial passages (A), increased telomere shortening over serial passages (B), and increased beta-galactosidase staining (C).
Mentions: EGF was immobilized by amine coupling to an activated CM5 surface as previously described (Ferguson et al. 2000; PMID 10970856). sEGFRWT and sEGFRG428D proteins were flowed over this surface as well as a control surface at a flow rate of 10 μL/min for 10 min, which was sufficient to reach equilibrium even at low receptor concentrations. The relative responses shown in Figure5 were fit to Langmuir single-site binding isotherms in Prism 6.0 (Graphpad, La Jolla, CA, USA).

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