A hypomorphic Egfr allele does not ameliorate the palmoplantar keratoderma caused by SLURP1 deficiency

Abstract

Mutations in SLURP1, a secreted protein of keratinocytes, cause a palmoplantar keratoderma (PPK) known as mal de Meleda. Slurp1 deficiency in mice faithfully recapitulates the human disease, with increased keratinocyte proliferation and thickening of the epidermis on the volar surface of the paws. There has long been speculation that SLURP1 serves as a ligand for a receptor that regulates keratinocyte growth and differentiation. We were intrigued that mutations leading to increased signaling through the epidermal growth factor receptor (EGFR) cause PPK. Here, we sought to determine whether reducing EGFR signaling would ameliorate the PPK associated with SLURP1 deficiency. To address this issue, we bred Slurp1-deficient mice that were homozygous for a hypomorphic Egfr allele. The hypomorphic Egfr allele, which leads to reduced EGFR signaling in keratinocytes, did not ameliorate the PPK elicited by SLURP1 deficiency, suggesting that SLURP1 deficiency causes PPK independently (or downstream) from the EGFR pathway.

Punctate palmoplantar keratoderma: an unusual mutation causing an unusual phenotype

“…In this regard, it is of interest that PPKP1 has been associated with increased epidermal growth factor receptor (EGFR) signalling, 10 but a recent study ruled out a possible interaction between EGFR signalling and SLURP-1 function. 11 To conclude, we describe here the first nonstop mutation in SLURP1, resulting in a highly atypical phenotype, indistinguishable from AKE. These data need confirmation in additional cases.…”

“…It is possible that the unique mutation identified in the present study has a less severe effect on the secretion or function of SLURP‐1, resulting in an unusual phenotype. In this regard, it is of interest that PPKP1 has been associated with increased epidermal growth factor receptor (EGFR) signalling, but a recent study ruled out a possible interaction between EGFR signalling and SLURP‐1 function …”