Epithelial Genetics Group
Research
The McLean Lab focuses on human genetic disorders affecting the structure, function and differentiation of epithelial barrier tissues. Most of these conditions affect the epidermis and its appendages, such as hair, nail, sweat glands and sebaceous glands, however, a number affect other epithelial tissues such as those covering the cornea, mucous membranes and internal organs. Most of these disorders are caused by defects in genes encoding keratins - the intermediate filament cytoskeleton proteins of epithelial cells. Related disorders are caused by mutations in related genes encoding additional proteins associated with this important intracellular protein scaffold, whose primary function is to provide cells with mechanical resilience. Loss of or weakening of any components within this system lead to disorders associated with epithelial cell fragility and/or overgrowth (hyperkeratosis).

Examples of keratinzing disorders studied by the laboratory:

Epidermolysis bullosa simplex (EBS) is a inherited skin blistering disorder caused by genetic defects in the genes encoding keratins K5 or K14.

Pachyonychia congenita (PC) is an inherited disorder characterized by blistering and thickening (hyperkeratosis) of palm and sole skin, that can also affect the nails, oral mucosa and other epithelia.

Ichthyosis vulgaris (dry, scaly skin) is the most common keratinizing disorder and is arguably the most common monogenic disorders in humans.  The first filaggrin mutations to be identified were recently reported by this research group to be the cause ichthyosis vulgaris (Smith FJD et al., Nature Genetics, 38:337-342, 2006). These prevalent defects are carried by >9% of people of European origin and other less common filaggrin mutations are also emerging (Sandilands S et al., J Invest Dermatol, 126:1770-1775).

Atopic dermatitis (AD; eczema) is a major problem in dermatology since it affects up to 20% of children in the developed world.  Furthermore, the condition is often accompanied by a range of associated allergic symptoms that include allergies to food/dust/animals, asthma and hay fever.  Collectively, these atopic disease strongly impact on other areas of medicine.  In 2006, we showed for the first time that mutations in the filaggrin gene do not only cause ichthyosis vulgaris (Smith FJD et al., Nature Genetics, 38:337-342, 2006) but also predispose individuals to developing eczema, eczema-associated asthma and other related atopic conditions (Palmer CNA et al., Nature Genetics 38:441-446, 2006).  This work has been replicated by many other research groups and so filaggrin is increasingly recognised as the most important gene for atopic disease yet discovered.  Further genetic studies and therapy development based on the filaggrin gene is currently a major focus of the McLean group.  The filaggrin mutations so far identified are carried by several tens of millions of individuals worldwide and other mutations are now emerging and therefore, the filaggrin gene defects we have uncovered represent a major global healthcare burden.  New classes of drugs aimed at this novel target have the potential to reduce or prevent atopic diseases in the future within individuals carrying the predisposing filaggrin mutations. 
The main aims of the research group are as follows:

Identification of genes causing human keratinizing disorders
Providing improved diagnostics for patients with keratinizing disorders
Understanding the function of keratinocytes and their structural molecules
Gene therapy for human keratin disorders
Drug discovery for human keratinizing disorders

Our main achievements to date are:

Identification of several genes that cause monogenic disorders of epithelia
Identification of a major predisposing gene for a common genetic trait
Development of RNA-based gene therapy systems for keratin disorders
Development of drug assays for keratinizing disorders
100+ peer-reviewed publications in this field
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