8 April 2009

Mouse gene leads to new breakthrough in allergy research

An international collaboration between scientists at the University of Dundee and research groups in Ireland and Japan has discovered a genetic defect in mice that leads to allergic inflammation, comparable to that seen in human eczema and related allergic diseases.

The work confirms the role of the filaggrin gene in building up the barrier layers of the skin and demonstrates how mutations in this gene lead to conditions such as eczema. Researchers say their discovery will also allow them to identify key substances in the environment responsible for the huge increase in allergic disease seen in recent years.

Filaggrin is an abundant protein in the outermost layers of the skin and is produced by the filaggrin gene. Filaggrin’s function is to help produce the impermeable skin barrier layers present at the skin’s outermost surface and to keep these hydrated.

The skin’s inherent barrier function is akin to plastic or cling film - it acts to prevent water loss from the skin and importantly, to protect the body from foreign materials in the environment, such as allergens.

Lack of an intact skin barrier leads to allergens entering the body where they produce a range of allergic responses that include eczema, asthma, hay fever and other allergies.

The research collaboration team was led by Professor Irwin McLean, Professor of Human Genetics and Head of the Division of Molecular Medicine, at the University of Dundee. This new discovery is published on-line in the leading international journal Nature Genetics (6th April).

One in five children in Britain and other westernised nations suffer from eczema. Children with the condition have a predisposition to subsequently develop other allergic conditions, in particular asthma, but also hay fever and a range of other allergies. Treatment of these common conditions costs billions of pounds annually.

Previous groundbreaking work by key collaborators in the study - Professor McLean at Dundee, and Professor Alan Irvine at Our Lady’s Children Hospital and Trinity College Dublin - on Irish and British children with eczema had identified that that up to one in two cases of severe eczema in children is associated with genetic mutations in the filaggrin gene. These filaggrin gene defects are carried by more than 10% of the UK population, partly explaining why predisposition to eczema is so common.

In this new study the collaborative research team has identified an identical genetic mutation mechanism (technically known as a frame-shift mutation) in mice as was previously identified in children with eczema.

Detailed immunological studies on mice, in collaboration with mouse immunologist Professor Padraic Fallon, of Trinity College Dublin, revealed that this defect in the filaggrin gene leads to a loss of skin barrier integrity, making the skin more permeable to allergens (foreign materials). This eventually leads to the induction of allergic skin inflammation, comparable to that seen in human eczema and related allergic diseases.

Commenting on the significance of this discovery, Professor McLean said, “It is amazing to find a naturally occurring mouse mutant with a defect in the filaggrin gene that is essentially identical to filaggrin gene mutations in the human population.”

“Remarkably, these filaggrin-deficient mice show many of the hallmarks of human eczema and allergy, completely confirming our human genetics studies. Together, our human genetics studies, along with these new mouse genetics and immunology studies, confirm beyond all doubt that defective skin barrier function in general, and defects in the filaggrin gene in particular, is a major factor in predisposing individuals to eczema and related allergies.”

“The prevalence of eczema, asthma and allergies has increased considerably in recent decades and this is most likely due to unknown environmental factors. The filaggrin-deficient mice will allow us to identify key substances in the environment responsible for the huge increase in allergic disease.”

“These mice also represent a key to unlock new and improved therapies for eczema, asthma and allergies by targeting or supplementing the defective filaggrin gene. Drugs or other treatments aimed at the filaggrin gene are still some years away but this work is a major step in the right direction and should give hope to those with these distressing conditions.”

The Dundee component of the study was funded by the Medical Research Council, the British Skin Foundation and families affected by eczema from the Tayside region of Scotland.

Notes for editors:

Professor Irwin McLean, a human geneticist and skin biologist in Dundee, and Professor Alan Irvine, a clinical dermatologist and geneticist in Dublin, are the leading experts in the biology and genetics of the filaggrin gene and discovered its importance in human skin disease and allergy. They recently teamed up with Professor Padraic Fallon, a mouse immunologist in Dublin, to develop and characterise mouse models of eczema.

Normal people have two functional copies of the filaggrin gene (one copy inherited from each parent).

The McLean laboratory previously showed that >10% of the population carry genetic mutations that completely “knock out” the function of one of their filaggrin genes (Smith et al., Nature Genetics 38: 337-342, 2006). These people have skin that is drier than normal and may have mild scaling or flaking of the skin (mild ichthyosis vulgaris). About 1 in 90 of the UK population carry two filaggrin mutations and their skin completely lacks this protein. They have severely dry and flaky skin (severe ichthyosis vulgaris).

The McLean group went on to show that these same mutations are a major genetic predisposing factor for eczema (also known as atopic dermatitis) and other related allergic conditions, importantly including a form of asthma secondary to eczema (Palmer et al., Nature Genetics 38: 441-446, 2006).

The McLean laboratory subsequently showed that white European populations carry at least 5 common filaggrin mutations as well as many other rare mutations, all of which “knock out” the production of filaggrin protein in the skin and are important in genetic predisposition to eczema and related allergic diseases (Sandilands et al., Nature Genetics 39: 650-654, 2007).

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