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First published online April 16, 2004
doi: 10.1242/10.1242/jcs.01043

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Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients

D. W. Owens¹, N. J. Wilson¹, A. J. M. Hill¹, E. L. Rugg^1,*, R. M. Porter¹, A. M. Hutcheson², R. A. Quinlan^2,**, D. van Heel^3,, M. Parkes^3,, D. P. Jewell³, S. S. Campbell^4,¶, S. Ghosh^4,, J. Satsangi⁴ and E. B. Lane^1,

¹ Cancer Research UK Cell Structure Research Group, School of Life Science, University of Dundee, Dundee, DD1 5EH, UK
² Department of Biochemistry, MSI/WTB Complex, University of Dundee, Dundee, DD1 5EH, UK
³ Gastroenterology Unit, Nuffield Department of Medicine, The Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, UK
⁴ Gastrointestinal Unit, Department of Medical Science, Western General Hospital, Edinburgh, EH4 2XU, UK

Author for correspondence (e-mail: e.b.lane{at}dundee.ac.uk)

Accepted 5 December 2003

We have identified miss-sense mutations in keratin 8 in a subset of patients with inflammatory bowel disease (Crohn disease and ulcerative colitis). Inflammatory bowel diseases are a group of disorders that are polygenic in origin and involve intestinal epithelial breakdown. We investigated the possibility that these keratin mutations might contribute to the course of the disease by adversely affecting the keratin filament network that provides mechanical support to cells in epithelia. The mutations (Gly62 to Cys, Ile63 to Val and Lys464 to Asn) all lie outside the major mutation hotspots associated with severe disease in epidermal keratins, but using a combination of in vitro and cell culture assays we show that they all have detrimental effects on K8/K18 filament assembly in vitro and in cultured cells. The G62C mutation also gives rise to homodimer formation on oxidative stress to cultured intestinal epithelial cells, and homodimers are known to be polymerization incompetent. Impaired keratin assembly resulting from the K8 mutations found in some inflammatory bowel disease patients would be predicted to affect the maintenance and re-establishment of mechanical resilience in vivo, as required during keratin cytoskeleton remodeling in cell division and differentiation, which may lead to epithelial fragility in the gut. Simple epithelial keratins may thus be considered as candidates for genes contributing to a risk of inflammatory bowel disease.

Key words: Inflammatory bowel disease, K8 mutations, Chromosome 12q, IBD2, Crohn disease, Ulcerative colitis

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