ORPHA: 2337; DO: 0111707;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.12 | Palmoplantar keratoderma, Bothnian type | 600231 | Autosomal dominant | 3 | AQP5 | 600442 |
A number sign (#) is used with this entry because of evidence that the Bothnian type of palmoplantar keratoderma (PPKB) is caused by heterozygous mutation in the AQP5 gene (600442) on chromosome 12q13.
Hereditary palmoplantar keratoderma (PPK) is characterized by hyperkeratosis of the skin of palms and soles. Lind et al. (1994) described an autosomal dominant form of diffuse nonepidermolytic PPK, designated PPK type Bothnia (PPKB), which has a high prevalence of 0.3 to 0.55% in the 2 northernmost provinces of Sweden, situated to the west and the northwest of the Gulf of Bothnia. The Bothnian form is frequently complicated by fungal infections and lacks the histopathologic features distinctive of epidermolytic PPK (EPPK; 144200).
For discussion of phenotypic and genetic heterogeneity of palmoplantar keratoderma, see epidermolytic PPK (144200).
Lind et al. (1994) described 2 large Swedish families segregating a diffuse nonepidermolytic form of PPK. Affected family members presented a homogeneous PPK ranging from barely detectable to prominent, with the affected skin often showing a yellowish tint. The margin between normal and affected skin was distinct, sometimes with a papular border. A distinctive feature of the disorder was that the stratum corneum swelled and adopted a whitish spongy appearance under exposure to water. This spongy swelling was usually the first manifestation of the disorder, often observed in childhood, although not before 1 year of age. Scaling, erythema, and itching were usually signs of dermatophyte infections, which were found in 10 of 24 PPK patients examined.
By linkage analysis in 2 families segregating Bothnian-type PPK, Lind et al. (1994) demonstrated linkage to markers in a 14-cM interval on 12q11-q13 (maximum 2-point lod scores of 8.76 and 6.96 at a recombination fraction of 0.00 for markers D12S85 and D12S270, respectively). The authors noted that this region contains the keratin type II gene cluster (e.g., KRT1, 139350) as well as the retinoic acid receptor gamma gene (RARG; 180190).
The transmission pattern of PPKB in the families reported by Blaydon et al. (2013) was consistent with autosomal dominant inheritance.
Using linkage data in combination with exome sequencing followed by Sanger sequencing in families segregating autosomal dominant diffuse nonepidermolytic PPK, Blaydon et al. (2013) identified heterozygosity for 5 different missense mutations in the AQP5 gene (600442.0001-600442.0005) in affected members of 7 Swedish families, 3 British families, and a Scottish family. All of the mutations segregated with disease in the respective families and were not found in the dbSNP or 1000 Genomes Project databases. Immunohistochemical analyses revealed that the mutant AQP5 variants retained the ability to traffic to the plasma membrane; the analyses also showed an increase in levels of acetylated alpha-tubulin (see 602529) in a patient palm biopsy compared to a control palm, suggesting increased levels of microtubule stabilization in the diffuse NEPPK palmar epidermis.
Blaydon, D. C., Lind, L. K., Plagnol, V., Linton, K. J., Smith, F. J. D., Wilson, N. J., McLean, W. H. I., Munro, C. S., South, A. P., Leigh, I. M., O'Toole, E. A., Lundstrom, A., Kelsell, D. P. Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma. Am. J. Hum. Genet. 93: 330-335, 2013. [PubMed: 23830519] [Full Text: https://doi.org/10.1016/j.ajhg.2013.06.008]
Lind, L., Lundstrom, A., Hofer, P.-A., Holmgren, G. The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13. Hum. Molec. Genet. 3: 1789-1793, 1994. [PubMed: 7531539] [Full Text: https://doi.org/10.1093/hmg/3.10.1789]