Abstract
Background
Mutations in the gene encoding transglutaminase 1 (TG1) are responsible for various
types of autosomal recessive congenital ichthyosis (ARCI), such as lamellar ichthyosis
(LI), congenital ichthyosiform erythroderma (CIE) and some minor variants of ARCI.
A point mutation of R143C in the β-sandwich domain of TG1 has been often identified
in patients with LI or CIE.
Objective
To elucidate the effect of that point mutation on skin barrier structures and functions,
we generated mice with a point mutation of R142C, which corresponds to the R143C mutation
in human TG1.
Methods
A mouse line with the R142C point mutation in TG1 was established using a gene targeting
technique and the Cre-loxP system. The skin phenotypes were analyzed in homozygous mutant Tgm1R142C/R142C mice.
Results
In the skin of Tgm1R142C/R142C mice, expression of the mutant transcripts was comparable with wild-type or Tgm1+/R142C mice. However, the amount of mutated protein in the skin was markedly decreased in
Tgm1R142C/R142C mice, and the TG1 activity of Tgm1R142C/R142C keratinocytes was almost lost. Tgm1R142C/R142C mice exhibited morphological and functional skin barrier defects and neonatal lethality.
The stratum corneum of those mice lacked cornified envelopes, and loricrin, the major
structural component, failed to assemble at the corneocyte cell periphery. Tgm1R142C/R142C mice showed a marked increase in transepidermal water loss and their skin was easily
permeable to toluidine blue dye. The intercellular lipid lamellar structures of the
stratum corneum were irregular and the 13-nm periodic X-ray diffractions from the
stratum corneum lipid molecules were lost in vivo.
Conclusion
From these results, we suggest that the R142C mutation of TG1 reduces the enzyme stability
which is indispensable for development of the stratum corneum and skin barrier function
and for postnatal survival of mice.
Keywords
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Article info
Publication history
Published online: January 18, 2012
Accepted:
December 7,
2011
Received in revised form:
November 18,
2011
Received:
September 2,
2011
Footnotes
☆This work was supported by a Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) (20591359; 23591661); by a Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) (22791093); a High-Tech Research Center Grant; a grant from the Ministry of Health, Labour and Welfare, Health and Labour Sciences Research Grants for Research on intractable diseases.
Identification
Copyright
© 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Inc. All rights reserved.
