Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma.

Autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma is characterized by the adoption of a white, spongy appearance of affected areas upon exposure to water. After exome sequencing, missense mutations were identified in AQP5, encoding water-channel protein aquaporin-5 (AQP5). Protein-structure analysis indicates that these AQP5 variants have the potential to elicit an effect on normal channel regulation. Immunofluorescence data reveal the presence of AQP5 at the plasma membrane in the stratum granulosum of both normal and affected palmar epidermis, indicating that the altered AQP5 proteins are trafficked in the normal manner. We demonstrate here a role for AQP5 in the palmoplantar epidermis and propose that the altered AQP5 proteins retain the ability to form open channels in the cell membrane and conduct water.

Palmoplantar keratoderma of the Gamborg-Nielsen type is caused by mutations in the SLURP1 gene and represents a variant of Mal de Meleda.

Palmoplantar keratoderma of the Gamborg-Nielsen type (PPK-GN) is a rare autosomal recessive skin disorder described in patients from Sweden. Mal de Meleda (MDM) is also a rare autosomal recessive inherited PPK first reported in 5 families from the island of Meleda. The 2 conditions phenotypically overlap and are characterised by palmoplantar erythematous hyperkeratotic plaques. The genetic background giving rise to PPK-GN has hitherto been unknown, whereas MDM is known to be caused by mutations in the gene encoding secreted Ly-6/uPAR-related protein 1, SLURP-1. In the present study we scrutinised individuals affected by PPK-GN for mutations in the SLURP1 gene and identified 2 different mutations. Fourteen Swedish patients were homozygous for a previously described mutation, c.43T>C, while one individual was a compound heterozygote with one copy of a novel mutation, c.280T>A, in addition to one copy of the c.43T>C mutation. Hereby we confirm that PPK-GN is an allelic variant of MDM.