Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: Summary of mutations (including 23 novel) and modeling of TGase-1

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare cornification diseases. Germline mutations in TGM1 are the most common cause of ARCI in the US. TGM1 encodes for the TGase-1 enzyme that functions in the formation of the cornified cell envelope. We review the clinical manifestations as well as the molecular genetics of ARCI. In addition, we characterized 115 TGM1 mutations reported in 234 patients from diverse racial and ethnic backgrounds (Caucasion Americans, Norwegians, Swedish, Finnish, German, Swiss, French, Italian, Dutch, Portuguese, Hispanics, Iranian, Tunisian, Moroccan, Egyptian, Afghani, Hungarian, African-Americans, Korean, Japanese and South African). We report 23 novel mutations: 71 (62%) missense; twenty (17%) nonsense; nine (8%) deletion; eight (7%) splice-site and seven (6%) insertion. The c.877-2A>G was the most commonly reported TGM1 mutation accounting for 34 % (147/435) of all TGM1 mutant alleles reported to date. It had been shown that this mutation is common among North American and Norwegian patients due to a founder effect. Thirty-one percent (36/115) of all mutations and 41% (29/71) of missense mutations occurred in arginine residues in TGase-1. Forty-nine percent (35/71) of missense mutations were within CpG dinucleotides, and 74% (26/35) of these mutations were C> T or G>A transitions. We constructed a model of human TGase-1 and showed that all mutated arginines that reside in the two beta-barrel domains and two (R142 and R143) in the beta-sandwich are located at domain interfaces. In conclusion, this study expands the TGM1 mutation spectrum, summarizes the current knowledge of TGM1 mutations. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of 5′ methylated CpG dinucleotides. Structurally defective or attenuated cornified cell envelop have been shown in epidermal scales and appendages of ARCI patients with TGM1 mutations.

Regulation of the activities of the mammalian transglutaminase family of enzymes

“…Notable examples of inheritable disorders due to TG1 mutation include lamellar ichthyosis, autosomal recessive congenital ichthyosis, and nonbullous congenital erythrodermal ichthyosis. 50 Mutations are present on all domains of the protein, but strongly concentrate in the catalytic domain. Although most mutations await biochemical characterization to establish whether their effects are due to destabilization of the protein or altering regulatory sites, they effectively lead to reduced TG1 cross-linking activity during keratinocyte maturation.…”

“…The Figure 5. Model of the TG1 protein (generated using the Swiss-Model Automated Comparative Protein Modeling Server, 49 using the Factor XIII crystal structure 1EX0 as template, as described by Herman and coworkers 50 ).…”

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

“…Mutations in six genes have been described in non-HI ARCI to date, including TGM1 [Huber et al, 1995;Russell et al, 1995], ABCA12 [Lefèvre et al, 2003;Natsuga et al, 2007], NIPAL4 (also known as ICHTHYIN) [Lefèvre et al, 2004], CYP4F22 [Lefèvre, 2006], ALOX12B and ALOXE3 [Jobard et al, 2002]. Among them, TGM1 is thought to be the most prevalent causative gene [Fischer, 2009;Herman et al, 2009]. TGM1 encodes transglutaminase 1, which is expressed in the upper epidermis and catalyzes crosslinking of cornified cell envelope precursor proteins to form a cornified cell envelope in the stratum corneum [Herman et al, 2009].…”

“…Among them, TGM1 is thought to be the most prevalent causative gene [Fischer, 2009;Herman et al, 2009]. TGM1 encodes transglutaminase 1, which is expressed in the upper epidermis and catalyzes crosslinking of cornified cell envelope precursor proteins to form a cornified cell envelope in the stratum corneum [Herman et al, 2009]. NIPAL4 (or ICHTHYIN) encodes a protein of unknown function.…”

Type I Transglutaminase Accumulation in the Endoplasmic Reticulum May Be an Underlying Cause of Autosomal Recessive Congenital Ichthyosis

“…Over 90 different mutations of the Tgm1 gene have been identified in these patients (22). Many of these mutations are deletion or point mutations within the catalytic domain, but disease-associated mutations are also located in other segments of the TG1 protein that do not include residues that are directly required for activity (22,23). These mutations are associated with reduced TG1 level and activity in tissue and cultured cells derived from patients (24).…”