Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda.
Mal de Meleda is an autosomal recessive inflammatory and keratotic palmoplantar skin disorder due to mutations in the ARS B gene, encoding for SLURP-1 (secreted mammalian Ly-6/uPAR-related protein 1). SLURP-1 belongs to the Ly-6/uPAR superfamily of receptor and secreted proteins, which participate in signal transduction, immune cell activation or cellular adhesion. The high degree of structural similarity between SLURP-1 and the three fingers motif of snake neurotoxins and Lynx1 suggests that this protein interacts with the neuronal acetylcholine receptors. We found that SLURP-1 potentiates the human alpha 7 nicotinic acetylcholine receptors that are present in keratinocytes. These results identify SLURP-1 as a secreted epidermal neuromodulator which is likely to be essential for both epidermal homeostasis and inhibition of TNF-alpha release by macrophages during wound healing. This explains both the hyperproliferative as well as the inflammatory clinical phenotype of Mal de Meleda.
D000109:Acetylcholine / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000950:Antigens, Ly / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002999:Clone Cells; D018076:DNA, Complementary / Q000008:administration & dosage / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008845:Microinjections; D008958:Models, Molecular; D009036:Moths / Q000166:cytology; D009154:Mutation; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification / Q000494:pharmacology; D014982:Xenopus laevis / Q000502:physiology
D000950:Antigens, Ly; D018076:DNA, Complementary; D018377:Neurotransmitter Agents; D010455:Peptides; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; C048963:SLURP1 protein, human; D014568:Urokinase-Type Plasminogen Activator; D000109:Acetylcholine