A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases

Pierre A. Coulombe, M. Elizabeth Hutton, Robert Vassar, Elaine Fuchs

Research output: Contribution to journalArticle

Abstract

Previously we demonstrated that transgenic mice expressing a mutant keratin in the basal layer of their stratified squamous epithelia exhibited a phenotype bearing resemblance to a subclass (Dowling Meara) of a heterogeneous group of human skin disorders known as epidermolysis bullosa simplex (EBS) (Vassar, R., P. A. Coulombe, L. Degenstein, K. Albers, E. Fuchs. 1991. Cell. 64:365-380.). The extent to which subtypes of EBS diseases might be genetically related is unknown, although they all exhibit skin blistering as a consequence of basal cell cytolysis. We have now examined transgenic mice expressing a range of keratin mutants which perturb keratin filament assembly to varying degrees. We have generated phenotypes which include most subtypes of EBS, demonstrating for the first time that at least in mice, these diseases can be generated by different mutations within a single gene. A strong correlation existed between the severity of the disease and the extent to which the keratin filament network was disrupted, implicating perturbations in keratin networks as an essential component of these diseases. Some keratin mutants elicited subtle perturbations, with no signs of the tonofilament clumping typical of Dowling-Meara EBS and our previous transgenic mice. Importantly, basal cell cytolysis still occurred, thereby uncoupling cytolysis from the generation of large, insoluble cytoplasmic protein aggregates. Moreover, cell rupture occurred in a narrowly defined subnuclear zone, and seemed to involve three factors: (a) filament perturbation, (b) the columnar shape of the basal cell, and (c) physical trauma. This work provides the best evidence to date for a structural function of a cytoplasmic intermediate filament network, namely to impart mechanical integrity to the cell in the context of its tissue.

Original languageEnglish (US)
Pages (from-to)1661-1674
Number of pages14
JournalJournal of Cell Biology
Volume115
Issue number6
StatePublished - Dec 1991
Externally publishedYes

Fingerprint

Epidermolysis Bullosa Simplex
Keratins
Transgenic Mice
Intermediate Filaments
Phenotype
Skin
Cell Shape
Cytoskeleton
Rupture
Epithelium
Mutation
Wounds and Injuries

ASJC Scopus subject areas

  • Cell Biology

Cite this

Coulombe, P. A., Hutton, M. E., Vassar, R., & Fuchs, E. (1991). A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases. Journal of Cell Biology, 115(6), 1661-1674.

A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases. / Coulombe, Pierre A.; Hutton, M. Elizabeth; Vassar, Robert; Fuchs, Elaine.

In: Journal of Cell Biology, Vol. 115, No. 6, 12.1991, p. 1661-1674.

Research output: Contribution to journalArticle

Coulombe, PA, Hutton, ME, Vassar, R & Fuchs, E 1991, 'A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases', Journal of Cell Biology, vol. 115, no. 6, pp. 1661-1674.
Coulombe, Pierre A. ; Hutton, M. Elizabeth ; Vassar, Robert ; Fuchs, Elaine. / A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases. In: Journal of Cell Biology. 1991 ; Vol. 115, No. 6. pp. 1661-1674.
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