title: EGFR mutations cause a lethal syndrome of epithelial dysfunction with progeroid features.
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.
authors.affiliation: Department of Pediatrics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania ; Division of Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ganetzky
authors.affiliation: Division of Biochemical Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.
authors.forename: Erin
authors.initials: E
authors.lastname: Finn
authors.affiliation: Department of Biochemistry and Biophysics and Graduate Group in Biochemistry and Molecular Biophysics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania.
authors.forename: Atrish
authors.initials: A
authors.lastname: Bagchi
authors.affiliation: Division of Biochemical Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.
authors.forename: Ornella
authors.initials: O
authors.lastname: Zollo
authors.affiliation: Department of Pathology, The University of Pennsylvania Philadelphia, 19104, Pennsylvania.
authors.forename: Laura
authors.initials: L
authors.lastname: Conlin
authors.affiliation: Department of Pediatrics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania ; Division of Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.
authors.forename: Matthew
authors.initials: M
authors.lastname: Deardorff
authors.affiliation: Division of Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.
authors.forename: Margaret
authors.initials: M
authors.lastname: Harr
authors.affiliation: Department of Medical and Molecular Genetics, King's College London London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: St. John's Institute of Dermatology, King's College London London, United Kingdom ; The Centre for Dermatology and Genetic Medicine, University of Dundee Dundee, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.affiliation: Department of Pediatrics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania ; Division of Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.affiliation: Department of Biochemistry and Biophysics and Graduate Group in Biochemistry and Molecular Biophysics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lemmon
authors.affiliation: Department of Pediatrics, The University of Pennsylvania Philadelphia, 19104, Pennsylvania ; Division of Biochemical Genetics, The Children's Hospital of Philadelphia Philadelphia, 19104, Pennsylvania.
authors.forename: Neal
authors.initials: N
authors.lastname: Sondheimer
keywords: Epidermal growth factor; ichthyosis; progeria; receptor protein-tyrosine kinase