SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda

Summary Background Mal de Meleda (MDM) is palmoplantar erythrokeratoderma with an autosomal recessive inheritance and is caused by a mutation in the gene encoding SLURP‐1 (lymphocyte antigen 6/urokinase‐type plasminogen activator receptor related protein‐1). SLURP‐1 is an allosteric agonist to the nicotinic acetylcholine receptor (nAchR) and it regulates epidermal homeostasis. In addition, murine studies have shown that nAchR signalling is important for the regulation of T‐cell function. Among the family members, patients with the homozygous SLURP1 (previously known as ARS component B) mutation are prone to melanoma and viral infection, which might link to defective T‐cell function as well as a derangement of epidermal homeostasis. Objectives To investigate the association of the SLURP1 gene mutation with T‐cell activation in a Taiwanese family with MDM. To test that SLURP‐1 is essential for T‐cell activation. Methods Human peripheral blood mononuclear cells (PBMCs) were isolated from a Taiwanese MDM family bearing the G to A substitution in nucleotide 256 in the SLURP1 gene, corresponding to a glycine to arginine substitution at amino acid 86 (G86R) in the SLURP‐1 protein. PBMCs from homozygotes and wild‐type controls were stimulated with anti‐CD3/anti‐CD28 antibodies and the level of T‐cell activation was determined by the stimulation index. Results PBMCs with the heterozygous and homozygous SLURP‐1 G86R mutation had defective T‐cell activation. This was restored by the addition of 0·5 μg mL−1 recombinant human SLURP‐1 protein. Conclusions Patients with MDM with the homozygous SLURP‐1 G86R mutation may have an impaired T‐cell activation. The presence of wild‐type SLURP‐1 is essential for normal T‐cell activation.