Please use this identifier to cite or link to this item: https://doi.org/10.1242/jcs.01043
Title: Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients
Authors: Owens, D.W
Wilson, N.J
Hill, A.J.M
Rugg, E.L
Porter, R.M
Hutcheson, A.M
Quinlan, R.A
van Heel, D
Parkes, M
Jewell, D.P
Campbell, S.S
Ghosh, S
Satsangi, J
Lane, E.B 
Keywords: asparagine
cysteine
dimer
glycine
isoleucine
keratin
keratin 8
unclassified drug
valine
article
cell assay
cell differentiation
cell division
controlled study
Crohn disease
cytoskeleton
disease association
disease course
disease severity
enteritis
epidermis
epithelium cell
genetic risk
human
human cell
human cell culture
in vitro study
in vivo study
intermediate filament
intestine epithelium
intestine epithelium cell
missense mutation
oxidative stress
prediction
priority journal
protein polymerization
ulcerative colitis
Animals
Antibodies, Monoclonal
Base Sequence
Cell Differentiation
Chromosomes, Human, Pair 12
Colitis, Ulcerative
Crohn Disease
Dimerization
Electrophoresis, Polyacrylamide Gel
Humans
Inflammation
Inflammatory Bowel Diseases
Keratin-8
Keratins
Mice
Microfilaments
Models, Genetic
Molecular Sequence Data
Mutation
Oxidative Stress
Polymers
Protein Binding
Protein Conformation
Sequence Analysis, DNA
Time Factors
Transfection
Xenopus
Issue Date: 2004
Citation: Owens, D.W, Wilson, N.J, Hill, A.J.M, Rugg, E.L, Porter, R.M, Hutcheson, A.M, Quinlan, R.A, van Heel, D, Parkes, M, Jewell, D.P, Campbell, S.S, Ghosh, S, Satsangi, J, Lane, E.B (2004). Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients. Journal of Cell Science 117 (10) : 1989-1999. ScholarBank@NUS Repository. https://doi.org/10.1242/jcs.01043
Rights: Attribution 4.0 International
Abstract: 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.
Source Title: Journal of Cell Science
URI: https://scholarbank.nus.edu.sg/handle/10635/181109
ISSN: 00219533
DOI: 10.1242/jcs.01043
Rights: Attribution 4.0 International
Appears in Collections:Elements
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