Research Highlights

Cellular protein linked to rare skin disease

Published online 14 October 2012

Habib Maroon

© Nature Genetics

Punctate Palmoplantar Keratoderma type 1 (PPKP1) is a rare heritable disease in which the outer layer of the skin grows unchecked forming many raindrop-shaped lesions on the palms of the hands and the soles of the feet which can be severe, painful and debilitating.

Analysing 18 families from around the world, a multinational team of scientists led by Irwin McLean of the University of Dundee, UK, and including Lobna Boussofara and Mohamed Denguezli of the Farhat Hached University Hospital in Sousse, Tunisia, have found that PPKP1 is caused by loss-of-function mutations in one copy of the gene AAGAB. This gene encodes the protein p34, which interacts with adaptor protein complexes responsible for sorting intracellular vesicles.

Experiments in a human skin cell line show how deficiency of the protein p34 caused PPKP1. Its depletion from these cells leads to increased cell proliferation. The scientists suggest that the recycling of an activated growth factor receptor (EGFR), a process which involves endosomes, a type of intracellular vesicle, is disrupted in PPKP1 patients. In p34 deficient cells, a massive build-up of EGFR, measured as greater than 10 fold of total EGFR protein, occurs. This breakdown in the regulation of EGFR signalling explains the increased cellular proliferation, although other pathways may also be involved.

These findings will allow for an improved diagnosis of PPKP1, and aid the development of treatments. "The fact that growth factor signalling is involved opens up avenues to potentially treat this and similar conditions by either directly blocking the receptors involved or perhaps targeting molecules downstream, using small molecule drugs," says Irwin McLean.


  1. Pohler, E., et al. Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nature Genetics (2012) doi:10.1038/ng.2444