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Mutation Identified That Causes Skin Hyperproliferation

Scientists have identified a mutation in a gene that causes patches of very thick skin to appear on the palms and soles of affected people. This skin disorder is related, albeit in a much milder form, to that of the Indonesian ‘Tree Man’, Dede Koswara[. These thick rough skin patches on hands and feet steadily increase in number as a person ages and often coalesce to form larger lesions. In severe cases, these lesions can be painful and debilitating.

The team of scientists from A*STAR’s Institute of Medical Biology (IMB), in collaboration with hospitals and research centres from the UK, Japan and , found that this skin disorder, called punctate palmoplantar keratoderma (punctate ), is caused by mutations in the AAGAB gene. Punctate is a rare subtype of palmoplantar keratoderma (), which appears in subtly different forms and seems to have several possible causes. Several families in Singapore are afflicted by different types of PPKs and scientists at A*STAR have also been working with doctors at the National Skin Centre to understand the different forms of this skin disorder.

The identification of the gene mutation will help scientists to better understand the molecular basis of this disease and potentially lead to a suitable treatment. This discovery will improve the classification and diagnosis of PPKs as well as open the door to novel approaches to treatment of skin disorders. These findings were published in the recent advanced online issue of Nature Genetics.

The scientists analyzed DNA samples collected from 18 families from Scotland, Ireland, Japan and Tunisia who had punctate PPK. They showed that the AAGAB gene, which encodes the protein p34, was expressed in skin and had a role in the control of cell division. The depletion in AAGAB led to a deficiency in p34, which resulted in increased cell proliferation in the outer layers of skin, the epidermis, because of an increased growth signal coming through the epidermal growth factor receptor (EGFR). The disruption of EGFR signalling is a feature of abnormal cell proliferation and the discovery suggests that PPK may be a benign form of hyperproliferation.

Dr Bruno Reversade, Senior Principal Investigator at IMB, who is a member of the team said, “The study of rare genetic disorders can often provide unexpected links; the phenotype seen in punctate PPK patients bears striking resemblance to common warts, and it is tempting to speculate that HPV could also hijack the same pathways to induce skin hyperproliferation. This discovery also demonstrates that EGFR, a hallmark of skin cancer, is part of the molecular explanation of the overproliferation of lesions in PKK patients.”

“Every time we find a new genetic mutation that causes a skin disorder, it helps patients and their families to demystify their condition,” said Prof Birgitte Lane, Executive Director of IMB. “With scientists and doctors working towards common goals like this, we find better treatments for more and more of these rare conditions.”


The research findings described in this news release can be found on Nature Genetics’s website under the title “Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctuate palmoplantar keratoderma” by Elizabeth Pohler(1,2,) Ons Mamai(3), Jennifer Hirst(4), Mozheh Zamiri(5), Helen Horn(6), Toshifumi Nomura(7), Alan D Irvine(8,9,) Benvon E Moran(8), Neil J Wilson(1,2, ) Frances J D Smith(1,2,) Christabelle S M Goh (1,2,) Aileen Sandilands (1,2,) Christian Cole (1,2,10,) Geoffrey J Barton (10), Alan T Evans (11), Hiroshi Shimizu (7), Masashi Akiyama (12) , Akihiro Suehiro (13), Izumi Konohana (14), Mohammad Shboul (15), Sebastien Teissier (15), Lobna Boussofara (16), Mohamed Denguezli (16), Ali Saad (3), Moez Gribaa (3), Patricia J Dopping-Hepenstal (17), John A McGrath (18), Sara J Brown (1,2), David R Goudie (19), Bruno Reversade (15,20), Colin S Munro (21) & W H Irwin McLean (1,2).
1 Department of Dermatology, College of Life Sciences, University of , , UK
2 Department of Genetic Medicine, College of Medicine, Dentistry & Nursing, University of Dundee, Dundee, UK
3 Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, , Tunisia.
4 , University of Cambridge, Cambridge, UK
5 Department of Dermatology, University Hospital Crosshouse, Kilmarnock, UK
6 Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, UK
7 Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
8 Department of Paediatric Dermatology, Our Lady’s Children’s Hospital, Dublin, Ireland
9 , Trinity College Dublin, Dublin, Ireland
10 Bioinformatics Research Group, Division of Biochemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK
11 Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK
12 Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
13 Department of Dermatology, Otsu Municipal Hospital, Otsu, Japan
14 Department of Dermatology, Hiratsuka Municipal Hospital, Hiratsuka, Japan
15 Institute of Medical Biology, A*STAR, Singapore
16 Department of Dermatology and Venerology, Farhat Hached University Hospital, Sousse, Tunisia
17 GSTS Pathology, St. Thomas’ Hospital, London, UK
18 St. John’s Institute of Dermatology, King’s College London, London, UK
19 Human Genetics Unit, Ninewells Hospital and Medical School, Dundee, UK
20 Department of Paediatrics, National University of Singapore, Singapore
21 Department of Dermatology, Southern General Hospital, Glasgow, UK.
Agency for Science, Technology and Research (A*STAR), Singapore