TRANSGLUTAMINASE-1 MUTATIONS IN AUTOSOMAL RECESSIVE CONGENITAL ICHTHYOSIS - PRIVATE AND RECURRENT MUTATIONS IN AN ISOLATED POPULATION

Autosomal recessive congenital ichthyosis (ARCI) is a rare, heterogeno us keratinization disorder of the skin, classically divided into two c linical subtypes, lamellar ichthyosis (LI) and nonbullous congenital i chthyosiformis erythroderma (CIE). Recently, strong evidence for the i nvolvement of the transglutaminase 1 gene (TGM1) in LI has evolved. We have studied ARCI in the isolated Finnish population, in which recess ive disorders are often caused by single mutations enriched by a found er effect. Surprisingly, five different mutations of TGM1 (Arg141His, Arg142Cys, Gly217Ser, Val378Leu, and Arg395Leu) were found in Finnish ARCI patients. In addition to affected LI patients, we also identified TGM1 mutations in CIE patients. Moreover, haplotype analysis of the c hromosomes carrying the most common mutation, a C-->T transition chang ing Arg142 to Cys, revealed that the same mutation has been introduced twice in the Finnish population. In addition to this Arg142Cys mutati on, three other mutations, in Arg141 and Arg142, have been described e lsewhere, in other populations. These findings suggest that this regio n of TGM1 is more susceptible to mutation. The corresponding amino aci d sequence is conserved in other transglutaminases, but, for example, coagulation factor XIII (FXIII) mutations do not cluster in this regio n. Protein modeling of the Arg142Cys mutation suggested disruption or destabilization of the protein. In transfection studies, the closely r elated transglutaminase FXIII protein with the corresponding mutation was shown to be susceptible to degradation in COS cells, further suppo rting evidence of the destabilizing effect of the Arg142Cys mutation i n TGM1.