Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR
| Autor: | Penny E. Morton, Jemima E. Mellerio, Sachin N Patil, Michael A. Simpson, Lu Liu, Cheryl Wellington, Masashi Akiyama, James R. McMillan, Takuya Takeichi, Alya Abdul-Wahab, Sophia Aristodemou, John I. Harper, Maddy Parsons, Akemi Ishida-Yamamoto, Nerys Roberts, Amr Salam, Patrick Campbell, Gabriela Petrof, Laura E. Proudfoot, Sarawin Harnchoowong, Kristina L. Stone, W.H. Irwin McLean, Kingi Aminu, Kenneth Fong, John A. McGrath |
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| Rok vydání: | 2014 |
| Předmět: |
Keratinocytes
Male Pathology medicine.medical_specialty MAP Kinase Signaling System Cellular differentiation Biopsy Mutation Missense Inflammation Dermatitis Dermatology In Vitro Techniques Biochemistry Epithelium Fatal Outcome Downregulation and upregulation medicine Humans Epidermal growth factor receptor Molecular Biology Tissue homeostasis EGFR inhibitors Skin biology medicine.diagnostic_test Homozygote Cell Differentiation Cell Biology 3. Good health ErbB Receptors Child Preschool Skin biopsy biology.protein Signal transduction medicine.symptom Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | The Journal of investigative dermatology. 134(10) |
| ISSN: | 1523-1747 |
| Popis: | Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases, but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283 G>A; p.Gly428Asp) in a male infant with lifelong inflammation affecting the skin, bowel, and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules--similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient's skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died at the age of 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues. |
| Databáze: | OpenAIRE |
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