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SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda
1Department of Dermatology, National Taiwan University Hospital, Chung-Shan South Road, Taipei 100, Taiwan.
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.
Insights
Mal de Meleda (MDM) patients with SLURP-1 mutations show impaired T-cell activation. Restoring SLURP-1 protein function is essential for normal T-cell responses and epidermal homeostasis.
Area of Science:
- Immunology
- Genetics
- Dermatology
Background:
- Mal de Meleda (MDM) is an autosomal recessive palmoplantar erythrokeratoderma linked to SLURP-1 gene mutations.
- SLURP-1 regulates epidermal homeostasis and acts as an agonist for nicotinic acetylcholine receptors (nAchR).
- Defective SLURP-1 function may impair T-cell activity, increasing susceptibility to infections and melanoma.
Purpose of the Study:
- Investigate the link between SLURP1 gene mutations and T-cell activation in a Taiwanese MDM family.
- Determine if SLURP-1 is essential for T-cell activation.
Main Methods:
- Isolated peripheral blood mononuclear cells (PBMCs) from MDM family members with the SLURP1 G86R mutation and healthy controls.
- Stimulated PBMCs with anti-CD3/anti-CD28 antibodies.
- Assessed T-cell activation levels using the stimulation index.
Main Results:
- PBMCs from individuals with heterozygous and homozygous SLURP-1 G86R mutations exhibited defective T-cell activation.
- The addition of recombinant human SLURP-1 protein restored T-cell activation in affected PBMCs.
Conclusions:
- Homozygous SLURP-1 G86R mutations in MDM patients are associated with impaired T-cell activation.
- Wild-type SLURP-1 is crucial for maintaining normal T-cell activation and potentially epidermal homeostasis.
