A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice.

A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice. Research Abstract Details 

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A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice. Abstract Text:

Michael Hesse,Christine Grund,Harald Herrmann,Dominique ,Thomas Franz,M Bishr Omary,Thomas M Magin,

Mutations in genes encoding epidermal keratins cause skin disorders, while those in internal epithelial keratins, such as K8 and K18, are risk factors for liver diseases. The effect of dominant mutations in K8 or K18 during embryonic development and tissue homeostasis has not been examined so far. Here we demonstrate that the dominant mutation hK18 R89C, that is highly similar to hK14 R125C, causing EBS in humans, leads to cell type-specific lethality in mice, depending on the ratio of mutant to endogenous keratins. Mice expressing hK18 R89C in the absence of endogenous K19 and K18 died at mid-gestation from defects in trophoblast giant cells, accompanied by haematomas. A single, endogenous K18 allele rescued embryonic lethality but caused aggregation of keratins in all adult internal epithelia, surprisingly without spontaneous cell fragility. Closer analysis revealed that both filaments and aggregates coexisted in the same cell, depending on the ratio of mutant to endogenous keratins. Our results demonstrate that balanced overexpression of a wild-type keratin rescued the lethal consequences of a dominant-negative mutation. This has important implications for therapy approaches of keratinopathies, suggesting that suppressing the mutant allele is not necessary in vivo.

A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice. Publishing Authors By Initials

M Hesse,C Grund,H Herrmann,D ,T Franz,MB Omary,TM Magin,

For similar cells: trophoblasts research abstracts see: cells: trophoblasts research

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A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Experimental cell research

VOLUME: 313

Page Numbers: 3127-40

Journal Abbreviation: Exp. Cell Res.

ISSN: 0014-4827

DAY: 25

MONTH: 05

YEAR: 2007

A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice. Information

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LANGUAGE: eng

NlmUniqueID: 373226

A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice. Keywords Mesh Terms:

KEYWORDS: Trophoblasts

MESH TERMS: cytology

Chemical & Substance for Abstract: A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice. Information

Substance Name: Keratin-18

Registry Number: 0

Grant and Affiliation Information for A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice.

AFFILIATION: Institut für Physiologische Chemie, Abteilung für Zellbiochemie, Bonner Forum Biomedizin and LIMES, Rheinische Friedrich-Wilhelms-Universitaet, Nussallee 11, 53115 Bonn, Germany.

Country: United States

AGENCY: United States NIDDK

GRANT: DK 47918

ACRONYM: DK

MEDLINETA: Exp Cell Res

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