Palmoplantar keratoderma in Slurp1/Slurp2 double-knockout mice

Mutations in SLURP1, encoding a secreted protein of keratinocytes, cause a palmoplantar keratoderma (PPK) known as mal de Meleda [1]. When the link between SLURP1 mutations and mal de Meleda was uncovered, there was speculation that SLURP1 might be a ligand for a cell-surface receptor of keratinocytes [1]. Also, because the predicted structure of SLURP1 resembled cobra neurotoxins, there was speculation that SLURP1 might influence acetylcholine signaling [1]. Pharmacologic studies have supported that concept [2–4], but there is no clear evidence that SLURP1 binds to acetylcholine receptors, nor is it clear why perturbations in acetylcholine signaling would cause PPK.