Mutations in the gene encoding SLURP-1 in Mel de Meleda

Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characteri zed by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions , perioral erythema, brachydactyly and nail abnormalities, We report the re finement of our previously described interval of MDM on chromosome 8qter, a nd the identification of mutations in affected individuals in the ARS (comp onent B) gene, encoding a protein named SLURP-1, for secreted Ly-6/uPAR rel ated protein 1, This protein is a member of the Ly-G/uPAR superfamily, in w hich most members have been localized in a cluster on chromosome 8q24.3, Th e amino acid composition of SLURP-1 is homologous to that of toxins such as frog cytotoxin and snake venom neurotoxins and cardiotoxins. Three differe nt homozygous mutations (a deletion, a nonsense and a splice site mutation) were detected in 19 families of Algerian and Croatian origin, suggesting f ounder effects. Moreover, one of the common haplotypes presenting the same mutation was shared by families from both populations, Secreted and recepto r proteins of the Ly-G/uPAR superfamily have been implicated in transmembra ne signal transduction, cell activation and cell adhesion. This is the firs t instance of a secreted protein being involved in a PPK.