title: Transglutaminase 1 mutations in autosomal recessive congenital ichthyosis: private and recurrent mutations in an isolated population.
abstract: Autosomal recessive congenital ichthyosis (ARCI) is a rare, heterogenous keratinization disorder of the skin, classically divided into two clinical subtypes, lamellar ichthyosis (LI) and nonbullous congenital ichthyosiformis erythroderma (CIE). Recently, strong evidence for the involvement of the transglutaminase 1 gene (TGM1) in LI has evolved. We have studied ARCI in the isolated Finnish population, in which recessive disorders are often caused by single mutations enriched by a founder 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 chromosomes carrying the most common mutation, a C-->T transition changing Arg142 to Cys, revealed that the same mutation has been introduced twice in the Finnish population. In addition to this Arg142Cys mutation, three other mutations, in Arg141 and Arg142, have been described elsewhere, in other populations. These findings suggest that this region of TGM1 is more susceptible to mutation. The corresponding amino acid sequence is conserved in other transglutaminases, but, for example, coagulation factor XIII (FXIII) mutations do not cluster in this region. Protein modeling of the Arg142Cys mutation suggested disruption or destabilization of the protein. In transfection studies, the closely related transglutaminase FXIII protein with the corresponding mutation was shown to be susceptible to degradation in COS cells, further supporting evidence of the destabilizing effect of the Arg142Cys mutation in TGM1.
authors.affiliation: Department of Clinical Chemistry, University of Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Laiho
authors.forename: J
authors.initials: J
authors.lastname: Ignatius
authors.forename: H
authors.initials: H
authors.lastname: Mikkola
authors.forename: V C
authors.initials: VC
authors.lastname: Yee
authors.forename: D C
authors.initials: DC
authors.lastname: Teller
authors.forename: K M
authors.initials: KM
authors.lastname: Niemi
authors.forename: U
authors.initials: U
authors.lastname: Saarialho-Kere
authors.forename: J
authors.initials: J
authors.lastname: Kere
authors.forename: A
authors.initials: A
authors.lastname: Palotie
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D019556:COS Cells; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005387:Finland; D006239:Haplotypes; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000201:enzymology* / Q000235:genetics*; D007223:Infant; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis; D011503:Transglutaminases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011503:Transglutaminases; C105804:transglutaminase 1