Spotlight on Research for 2007

January 2007 (historical)

Mutations in Gene Cause Ichthyosis Vulgaris

Researchers have discovered that mutations in the filaggrin gene (FLG) are the cause of moderate or severe ichthyosis vulgaris (IV), the most common inherited disorder of keratinization, the process which forms the skin, hair and nails. FLG codes for the protein profilaggrin, a large molecule that is broken down to produce filaggrin, a protein normally found in the outermost layer of the skin. Filaggrin usually functions as a component of the skin barrier, protecting the body from water loss, allergens and infectious agents, but until now filaggrin had not been directly associated with any human disease.

The research, published in Nature Genetics, was conducted by a large group of investigators from the United Kingdom and the United States, including Richard B. Presland, Ph.D., of the University of Washington, Seattle, whose research is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Professor Irwin McLean of the University of Dundee in Scotland, the senior author of the study, together with 19 other researchers, studied 15 families from Ireland, Scotland and the United States. The family members had 1) the clinical features of IV: typically, dry and flaking skin and hyperlinear palms (extra skin creases in the palms); and 2) IV histological features, or signs recognizable in the tissues when examined under a microscope. Analyzing blood and skin biopsy samples from the family members, the researchers found two different mutations in FLG, with IV being observed in both the homozygous (both copies of the gene are mutated) and heterozygous (only one copy of the gene is mutated) conditions. Individuals who were homozygous for the FLG mutation had more severe skin disease than heterozygous individuals. In certain individuals homozygous for the FLG mutation, there was a complete loss of filaggrin protein and impaired formation of the skin. The scientists concluded that, in populations of European descent, IV seems to be predominantly caused by mutation of the filaggrin gene.

The scientists undertook this study because a growing body of evidence led them to suspect the FLG gene might be causing the disease. Filaggrin is one of the proteins in the epidermal differentiations complex (EDC). The EDC, located on chromosome 1q21, is a cluster of genes responsible for many of the proteins associated with the structure of the skin. Previous studies demonstrated that filaggrin was absent or reduced in the skin cells of individuals with IV, and genetic linkage studies had mapped the disease gene to chromosome 1q21 where FLG is located. A mutant mouse known as flaky tail (which lacks filaggrin protein) has many of the same skin problems as in human IV, further suggesting that a FLG mutation may cause IV.

Additionally, IV is frequently associated with atopic dermatitis, or eczema. The authors suggest that filaggrin may be a factor in atopic dermatitis and other skin disorders with a genetic component. More recent work, the authors say, has indeed shown that FLG mutations are common in atopic dermatitis and appear to be strong predisposing genetic factors for this disease. Thus, loss of filaggrin protein is also associated with eczema, probably because the skin barrier is compromised.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at

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Smith F, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nature Genetics 2006;38(3):337-342.