Eczema and asthma linked to key filaggrin gene

6 April 2006

Researchers at Dundee University's Human Genetics Department, working in collaboration with others in Glasgow, Dublin, Seattle and Copenhagen, have identified mutations that cause a common skin disorder and predispose individuals to eczema and a related form of asthma. This work has been published in two consecutive papers in the March and April editions of Nature Genetics.

The first paper confirms the genetic cause of hereditary ichthyosis vulgaris [Smith FJ (2006) Nat Genet. 38, 337-42]. This condition, which causes the skin to become dry and scaly, is one of the most frequent single-gene disorders in humans with an estimated UK incidence of 1 in 250 children. It is an autosomal dominant genetic disorder that develops in early childhood. Around 120,000 people within the UK have a severe form of the condition, and around 5 million have a milder form. Existing evidence already strongly suggested that the filaggrin gene (FLG) was involved in ichthyosis vulgaris. Filaggrin (filament aggregating protein) is a key protein in the formation of the outer layers of the skin, especially the outermost protective barrier, which prevents water loss and blocks entry of infectious and allergenic agents. However, the long and repetitive DNA sequence of the FLG gene has previously impeded analysis.

The researchers looked at the FLG gene from seven unrelated ichthyosis vulgaris families and eight further isolated cases (for which no family history was available) from Ireland, Scotland and the USA. Using advanced forms of sequencing, they were able to identify a nonsense mutation, R501X, in affected individuals. Some patients with severe phenotypes were found to be homozygous for R501X, whilst others with milder phenotypes were all heterozygous for the mutation. Only two heterozygotes were identified with no clinical phenotype, leading to an estimate of 90% penetrance, although the authors caution that this figure may be an overestimate. Further sequence analysis of all the heterozygotes led to the identification of a second mutation, 2282del4. R501X/2282del4 compound heterozygotes showed severe phenotypes similar to those of the R501X homozygotes. Both mutations cause premature termination of the filaggrin protein. Analysis of skin samples from an R501X homozygote and an R501X/2282del4 compound heterozygote showed an identical loss of functional filaggrin protein, although a severely truncated version of the protein was present.

The combined allele frequency of the mutant alleles in the corresponding Caucasian populations was found to be relatively high at 3.7%. A semi-dominant mode of inheritance of the mutations is proposed, with incomplete penetrance, whereby heterozygotes have absent to mild ichthyosis vulgaris whilst homozygotes or compound heterozygotes for the mutant allele/s have moderate to severe disease. It is suggested that, since the number of repeats within the human FLG gene is known to vary between individuals (10

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