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.

Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families

“…Both haplotypes A and B are present in a very small geographical region, in adjacent communities in an old sparsely populated region and haplotype B also in a more recently inhabited region. Interestingly, a similar situation has been observed in autosomal recessive congenital ichtyosis: an identical transglutaminase 1 gene (TGM1) mutation is present in two haplotypes in the Savo region in southeastern Finland, and one of the haplotypes is also present in central Finland 36 that was inhabited in the 16th century mainly by population movement from South Savo. The small symbols represent birthplaces of the earliest known cancer generation (two symbols for each family) and the large symbols birthplaces of the proband, if information of the previous generations was not available.…”

Harlequin ichthyosis and other autosomal recessive congenital ichthyoses: The underlying genetic defects and pathomechanisms

“…Most TGM1 mutations reported in LI families are located in the core domain or upstream of it [4,27]. TGM1 mutations were also reported to lead to an NBCIE phenotype in a small number of the families [28][29][30] and defective transglutaminase 1 is not specific for the classic LI phenotype. We can hypothesize that serious loss of transglutaminase 1 activity might lead to the classic LI phenotype [27] and a partial loss of transglutaminse 1 activity to a mild form of LI [31] or a phenotype of NBCIE [29].…”

“…Mutations in transglutaminase 1 gene result in phenotypes with both LI [2,3] and NBCIE [28][29][30].…”

Lamellar Ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus

“…4 Transglutaminase 1 (TGM1) was the first gene demonstrated to cause LI. [4][5][6][7][8][9] This gene directs the construction of the cornified envelope, a protein structure underneath the plasma membrane of keratinocytes which forms during their late-stage terminal differentiation. 10 However, TGM1 and other known genes involved in cornified envelope construction were firmly excluded in many other LI families (and also in families subclassified as erythrodermic LI).…”