Mal de Meleda: genetic haplotype analysis and clinicopathological findings in cases originating from the island of Mljet (Meleda), Croatia

BACKGROUND: Mal de Meleda (keratoderma palmoplantaris transgrediens) is an autosomal recessive disorder, first described on the island of Mljet (Meleda), Croatia. The candidate region for the gene responsible for this disorder was found on the chromosome 8qter, and the responsible mutations have recently been identified in 12 Algerian and 7 Croatian families. OBJECTIVES: To fully characterize all 12 living cases originating from the original setting of the disease, the island of Mljet, in the light of new findings and using modern diagnostic technology. PATIENTS AND METHODS: Twelve patients and 37 family members were identified over the period 1998-1999, interviewed and examined. RESULTS: The reconstruction of 8 genealogies suggests a common ancestry of all cases but one. The clinical presentation and pathologic findings of these cases are described in detail and are consistent with previous reports. Symptoms and signs were found to be milder in non-manual workers who had applied continuous symptomatic treatment. Blood samples were taken from 8 cases and 16 close relatives for genetic studies. These confirmed a shared haplotype in all cases, but in none of 17 unaffected control individuals, near the marker D8S1751 on chromosome 8. CONCLUSIONS: This review characterizes mal de Meleda in its original setting and shows that the sporadic cases found in the regions of medieval trade routes of the Republic of Dubrovnik (Middle East and Northern Africa) carry the same mutation as the patients from Mljet Island, Croatia

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

Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities. We report the refinement of our previously described interval of MDM on chromosome 8qter, and the identification of mutations in affected individuals in the ARS (component B) gene, encoding a protein named SLURP-1, for secreted Ly-6/uPAR related protein 1. This protein is a member of the Ly-6/uPAR superfamily, in which most members have been localized in a cluster on chromosome 8q24.3. The amino acid composition of SLURP-1 is homologous to that of toxins such as frog cytotoxin and snake venom neurotoxins and cardiotoxins. Three different homozygous mutations (a deletion, a nonsense and a splice site mutation) were detected in 19 families of Algerian and Croatian origin, suggesting founder effects. Moreover, one of the common haplotypes presenting the same mutation was shared by families from both populations. Secreted and receptor proteins of the Ly-6/uPAR superfamily have been implicated in transmembrane signal transduction, cell activation and cell adhesion. This is the first instance of a secreted protein being involved in a PPK

SLURP1 is a late marker of epidermal differentiation and is absent in Mal de Meleda

SLURP1 is a secreted member of the LY6/PLAUR protein family. Mutations in the SLURP1 gene are the cause of Mal de Meleda (MDM), a rare autosomal recessive genetic disease, characterized by inflammatory palmoplantar keratoderma. In this study, we have analyzed the expression of SLURP1 in normal and MDM skin. SLURP1 was found to be a marker of late differentiation, predominantly expressed in the granular layer of skin, notably the acrosyringium. Moreover, SLURP1 was also identified in several biological fluids such as sweat, saliva, tears, and urine from normal volunteers. In palmoplantar sections from MDM patients, as well as in their sweat, mutant SLURP1, including the new variant R71H-SLURP1, was either absent or barely detectable. Transfected human embryonic kidney 293T cells expressed the MDM mutant SLURP1 containing the single amino-acid substitution G86R but did not tolerate the MDM mutation W15R located in the signal peptide. Thus, most MDM mutations in SLURP1 affect either the expression, integrity, or stability of the protein, suggesting that a simple immunologic test could be used as a rapid screening procedure