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

Rebecca Ganetzky,Laura Conlin,Neal Sondheimer,Ornella Zollo,John A Mcgrath,Matthew Deardorff,Michael A Simpson,Erin Finn,Elaine Zackai,Atrish Bagchi,Mark A Lemmon,Margaret Harr

doi:10.1002/mgg3.156

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.

Highlights

Epidermal growth factor receptor (EGFR, OMIM 131550) plays critical roles in organismal development by transducing an extracellular signal to guide growth and differentiation of multiple tissue types (Sibilia et al 2007)
We evaluated the replicative capacity of patient and control fibroblasts by serially passaging cells and found that the EGFRGly428Asp patient cell line had impaired replication at late passage when compared to control cells (Fig. 5B)
Evidence in this study and in the analysis of an additional affected patient from the same ethnic background shows that a failure of epidermal growth factor receptor (EGFR) signaling leads to a complex phenotype with marked defects in epithelial formation and gut integrity

Summary

Introduction

Epidermal growth factor receptor (EGFR, OMIM 131550) plays critical roles in organismal development by transducing an extracellular signal to guide growth and differentiation of multiple tissue types (Sibilia et al 2007). The disruption of EGFR in mouse model systems causes strainspecific lethality and prominent effects upon heart, brain, and epithelial tissues (Sibilia and Wagner 1995; Threadgill et al 1995; Hansen et al 1997). Occurring mouse models with point mutations in EGFR (waved-2) have defects in hair and eyelid opening (Luetteke et al 1994). Studies of the role of EGFR in organ and tissue development have been nearly overshadowed by the discovery of the role of activating EGFR mutations in tumor biology (Pao and Chmielecki 2010). EGFR is overexpressed in a range of epithelial tumor types, and somatic mutations in EGFR were found to mediate the susceptibility of a 2015 The Authors.

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