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

[lamellar ichthyosis]

Mutations in the gene encoding transglutaminase 1 (TG 1 ) 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 R 143 C in the β-sandwich domain of TG 1 has been often identified in patients with LI or CIE .To elucidate the effect of that point mutation on skin barrier structures and functions , we generated mice with a point mutation of R 142 C , which corresponds to the R 143 C mutation in human TG 1 .A mouse line with the R 142 C point mutation in TG 1 was established using a gene targeting technique and the Cre-lox P system . The skin phenotypes were analyzed in homozygous mutant Tgm 1 (R 142 C /R 142 C ) mice .In the skin of Tgm 1 (R 142 C /R 142 C ) mice , expression of the mutant transcripts was comparable with wild-type or Tgm 1 (+/R 142 C ) mice . However , the amount of mutated protein in the skin was markedly decreased in Tgm 1 (R 142 C /R 142 C ) mice , and the TG 1 activity of Tgm 1 (R 142 C /R 142 C ) keratinocytes was almost lost . Tgm 1 (R 142 C /R 142 C ) 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 . Tgm 1 (R 142 C /R 142 C ) 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 .From these results , we suggest that the R 142 C mutation of TG 1 reduces the enzyme stability which is indispensable for development of the stratum corneum and skin barrier function and for postnatal survival of mice .