Knocking-in the R142C mutation in transglutaminase 1 disrupts the stratum corneum barrier and postnatal survival of mice.

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- lox P system. The skin phenotypes were analyzed in homozygous mutant Tgm1 R142C/R142C mice. Results In the skin of Tgm1 R142C/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 Tgm1 R142C/R142C mice, and the TG1 activity of Tgm1 R142C/R142C keratinocytes was almost lost. Tgm1 R142C/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. Tgm1 R142C/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.