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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

Downstream targets of EGF, Jun (dark bars), Myc (grey bars), and Fos (light bars), are increased in response to stimulation with EGF in control cells, but not patient cells (A). Growth of control cells in a minimal media of insulin, dexamethasone, and ascorbic acid (IAD) (lightest line) can be rescued with EGF treatment (IADE) (middle line) (B), whereas patient cell growth cannot be rescued with EGF (middle line) (C).
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fig02: Downstream targets of EGF, Jun (dark bars), Myc (grey bars), and Fos (light bars), are increased in response to stimulation with EGF in control cells, but not patient cells (A). Growth of control cells in a minimal media of insulin, dexamethasone, and ascorbic acid (IAD) (lightest line) can be rescued with EGF treatment (IADE) (middle line) (B), whereas patient cell growth cannot be rescued with EGF (middle line) (C).

Mentions: Binding of EGF by EGFR activates a sequence of receptor tyrosine kinases and regulates nuclear transcription. Dermal fibroblast cell lines were generated from patient 2 and a control individual. EGF-induced expression of JUN, FOS, and MYC were assessed using real-time PCR. Despite robustly inducing these immediate early gene products in control fibroblasts as expected (Fig.2A), EGF was not able to increase their expression in the patient-derived cells (JUN, P = 0.0001 FOS: P < 0.0001, MYC: P < 0.0001; Fig.2A). Similarly, whereas EGF supplementation will allow control fibroblasts to grow in a minimal medium containing insulin, ascorbic acid, and dexamethasone (IAD), EGF failed to support the growth of patient-derived cells in the same medium (Fig.2B and C) – reflecting a loss of EGFR function.


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)

Downstream targets of EGF, Jun (dark bars), Myc (grey bars), and Fos (light bars), are increased in response to stimulation with EGF in control cells, but not patient cells (A). Growth of control cells in a minimal media of insulin, dexamethasone, and ascorbic acid (IAD) (lightest line) can be rescued with EGF treatment (IADE) (middle line) (B), whereas patient cell growth cannot be rescued with EGF (middle line) (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: Downstream targets of EGF, Jun (dark bars), Myc (grey bars), and Fos (light bars), are increased in response to stimulation with EGF in control cells, but not patient cells (A). Growth of control cells in a minimal media of insulin, dexamethasone, and ascorbic acid (IAD) (lightest line) can be rescued with EGF treatment (IADE) (middle line) (B), whereas patient cell growth cannot be rescued with EGF (middle line) (C).
Mentions: Binding of EGF by EGFR activates a sequence of receptor tyrosine kinases and regulates nuclear transcription. Dermal fibroblast cell lines were generated from patient 2 and a control individual. EGF-induced expression of JUN, FOS, and MYC were assessed using real-time PCR. Despite robustly inducing these immediate early gene products in control fibroblasts as expected (Fig.2A), EGF was not able to increase their expression in the patient-derived cells (JUN, P = 0.0001 FOS: P < 0.0001, MYC: P < 0.0001; Fig.2A). Similarly, whereas EGF supplementation will allow control fibroblasts to grow in a minimal medium containing insulin, ascorbic acid, and dexamethasone (IAD), EGF failed to support the growth of patient-derived cells in the same medium (Fig.2B and C) – reflecting a loss of EGFR function.

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