Transglutaminase diseases: from biochemistry to the bedside.

In humans, 9 members of the transglutaminase (TG) family have been identified, of which 8 [factor XIII (FXIII)A and TG1-TG7] catalyze post-translational protein-modifying reactions, and 1 does not (protein 4.2). The TG enzymatic activities considered in our discussion of human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. Except for TG7, which remains poorly studied, all individual TG members have been correlated with disparate human diseases that arise from either TG function or lack of function. Loss of TG function is associated with numerous orphan diseases that affect a relatively small number of individuals: loss of FXIIIa (transamidase-activated form) crosslinking leads to defects in blood coagulation in FXIII deficiency; loss of TG1 and TG5 cross linking leads to defects in epidermal cornification in lamellar ichthyosis and acral peeling skin syndrome, respectively; loss of TG3 crosslinking in hair-cuticle formation leads to uncombable hair syndrome; the predicted loss of TG6 crosslinking leads to spinocerebellar ataxia-35; and loss of the structural erythrocyte membrane protein, protein 4.2, leads to hereditary spherocytosis type 5. The enzymatic activity of TG2 is involved in the exacerbation of celiac disease and in at least 1 case of hemoglobinopathy, characterized by shortened erythrocyte lifespan. TGs are also autoantigens in a number of immune diseases, resulting in the production of autoantibodies against FXIIIa in acquired FXIII deficiency, TG2 in celiac disease, TG3 in dermatitis herpetiformis, TG4 in autoimmume polyglandular syndrome type 1, and TG6 in gluten axonal neuropathy and gluten ataxia. Much still remains to be learned and confirmed with respect to disease mechanisms, particularly with respect to TG-related immune diseases, in which development of isozyme-specific inhibitors may be useful for treatment.-Lorand, L., Iismaa, S. E. Transglutaminase diseases: from biochemistry to the bedside.