University of Dundee

Genetic diagnostics for patients with inherited keratin skin disorders

Thanks to work carried out by researchers at the University of Dundee, patients affected by inherited keratin skin disorders can now obtain a definitive diagnosis through the provision of genetic testing, which has been pivotal in enabling accurate treatment of these disorders and driving the development of targeted therapeutics

Keratinocyte cells, found in the outer layer of the skin, maintain the skin’s integrity and help it withstand the mechanical and chemical forces it is subjected to every day.  Much of this strength comes from a dense meshwork of a family of proteins called keratins.  Cutting edge genome wide and candidate gene linkage analysis led by Professor Irwin McLean FRS FRSE FMedSci and Professor Birgit Lane FRSE FMedSci at the University of Dundee directly showed that mutations in several keratin proteins cause a variety of skin fragility conditions including Weber-Cockayne Epidermolysis Bullosa Simplex, Bullous Congenital Ichthyosiform Erythroderma. Painful blistering, overgrowth or scaling of the epidermis are some of the symptoms of these diseases and can significantly impact upon the patient’s life. Prior to identification of the causative mutations, diagnosis was often based upon clinical classification and hindered by significant variability in patient symptoms, even within the same family. The discovery that these skin disorders were due to mutation of a particular keratin protein has circumvented the ambiguity of diagnosis and enabled the ability to provide accurate genetic testing. It has also allowed the creation of accurate care and treatment plans, enabled targeted therapeutics to be developed, as well as providing the opportunity for prenatal genetic testing in suitable cases. This research was instrumental in making  UK-wide genetic testing for Epidermolysis Bullosa Simplex available since 2007.

A further skin disease that has been transformed by the work of the University of Dundee is pachyonychia congenita (PC). PC is an inherited skin disorder characterised by thickened toenails, calluses, blistering, thickened skin, and plantar pain. As well as identification of causative mutations in this disease, the laboratory of Prof McLean currently provides worldwide genetic testing for PC with funding from the charity the Pachyonychia Congentia Project. Moreover this research directly resulted in the creation of an approved patient registry for Pachyonychia Congenita in 2004. Lastly, collaboration between Professor McLean and researchers in Utah has led to the development of a siRNA therapy for PC, which entered clinical trials in January 2008. This is the first clinical trial for a skin condition and for specific silencing of a mutant gene to successfully demonstrate the efficacy and safety of siRNA treatment.