Epithelia form a variety of barrier tissues that are specialised to protect the human body from the external environment. The largest and most complex of epithelial tissues is the epidermis, which forms the first line of defense against the outside world. The keratinocyte cells of the epidermis are especially strong in order to resist the mechanical damage that the skin experiences in everyday life. Much of this strength comes from a dense meshwork of cytoplasmic intermediate filaments composed of keratin proteins. The cell-cell and cell-matrix attachment structures with which this cystoskeleton is connected, as well as a variety of enzymatic modifications of the network in certain locations, are also essential for the mechanical integrity of epithelial tissues. Genetic defects affecting any part of this system lead to fragility of the tissue, which manifests as blistering and/or hyperkeratosis (overgrowth) of the epithelium. Humans possess 54 functional keratin genes, 23 of which are now linked to genetic disorders, as well as scores of related cell junction and modifying proteins. Many of these disease associations were identified by members of this research group and all the genes we have identified have been translated into clinical diagnostic practice. For example, we run the international molecular diagnostic service for pachyonychia congenita and the UK-wide service for keratin disorders. Currently, we are using state-of-the-art whole exome sequencing methodologies to identify the causative genes in our extensive collection of unsolved keratinizing disorders obtained from our international network of collaborators.
We recently identified a new gene causing a painful and debilitating skin disorder, punctate palmoplantar keratoderma (also known as punctate PPK or PPKP1). The results were published in the top genetics journal Nature Genetics and widely reported in the media (click here for press release).
If you suffer from this or a similar skin condition causing overgrowth of thick skin on palms and soles (there are many related subtypes of this condition) and need patient support, genetic diagnosis or would like to get involved in research, please contact us.
- McLean WHI et al., (1995) Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nature Genetics 9:273-278. (PubMed ID: 7539673)
- Irvine AD and McLean WHI (1999) Human keratin diseases: the increasing spectrum of disease and the subtlety of phenotype-genotype correlation. Br J Dermatol 140:815-828 (PubMed ID: 10354017)
- Smith FJD et al., (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nature Genetics 38:337-342 (PubMed ID: 16444271)
- Wilson NJ et al., (2010) Keratin K6c mutations cause focal palmoplantar keratoderma. J Invest Dermatol 130:425-429 (PubMed ID: 19609311)
- McLean WHI and Moore CBT (2011) Keratin disorders: from gene to therapy. Hum Mol Genet 20:R189-197 (PubMed ID: 21890491)
- Pohler E et al., (2012) Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nature Genetics doi: 10.1038/ng.2444. [Epub ahead of print 14th Oct 2012] (PubMed ID: 23064416)