TY - JOUR
T1 - Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR
AU - Campbell, Patrick
AU - Morton, Penny E.
AU - Takeichi, Takuya
AU - Salam, Amr
AU - Roberts, Nerys
AU - Proudfoot, Laura E.
AU - Mellerio, Jemima E.
AU - Aminu, Kingi
AU - Wellington, Cheryl
AU - Patil, Sachin N.
AU - Akiyama, Masashi
AU - Liu, Lu
AU - McMillan, James R.
AU - Aristodemou, Sophia
AU - Ishida-Yamamoto, Akemi
AU - Abdul-Wahab, Alya
AU - Petrof, Gabriela
AU - Fong, Kenneth
AU - Harnchoowong, Sarawin
AU - Stone, Kristina L.
AU - Harper, John I.
AU - McLean, W. H.Irwin
AU - Simpson, Michael A.
AU - Parsons, Maddy
AU - McGrath, John A.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
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U2 - 10.1038/jid.2014.164
DO - 10.1038/jid.2014.164
M3 - Article
C2 - 24691054
AN - SCOPUS:84922391441
SN - 0022-202X
VL - 134
SP - 2570
EP - 2578
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 10
ER -