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 United States. TGM1 encodes for the TGase-1 enzyme that functions in the formation of the cornified cell envelope. Structurally defective or attenuated cornified cell envelop have been shown in epidermal scales and appendages of ARCI patients with TGM1 mutations. 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; 20 (17%) nonsense; 9 (8%) deletion; 8 (7%) splice-site, and 7 (6%) insertion. The c.877-2A>G was the most commonly reported TGM1 mutation accounting for 34% (147 of 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 of 115) of all mutations and 41% (29 of 71) of missense mutations occurred in arginine residues in TGase-1. Forty-nine percent (35 of 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 and 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.

Figure 1. TGM1 mutations associated with ARCI

A, TGM1 mutations reported in this study and the literature. B, TGM1 gene structure. C, TGAse-1 protein domains. Mutations reported in the present study (novel) are in red font and mutations in the literature are in blue. ¹Mutations found in patients diagnosed with ichthyosis with sparing of the lims/bathing suit ichthyosis. ²Mutations found in patients diagnosed with self-healing collodion baby. *indicates novel missense mutations.

Figure 2. Distribution of all arginine and non-arginine TGM1 mutations reported in the literature including this report

A, Structure of TGM1 with exons (black boxes) drawn to scale and the distribution of all reported TGM1 mutations. B, TGase-1 protein domains and the distribution of all reported TGM1 mutations. TGase-1 domain shown are based on the amino acid: Anchoring domain (1–92), β-sandwich domain (94–246), catalytic core domain (247–572), β-barrel 1 (573–688), β-barrel 2 (689–817). Triangles indicate active site residues C377, H436, and D459. “M” indicates myristolation motif of amino acids 47–54 (CCGCCSCR), and “P” indicates phosphorylation site S82. “X” indicates cleavage sites between amino acids S92 and R93 and N572 and R573. 5′, 124bp, and 3′, 197bp, untranslated regions are shown in grey.

Figure 3. Wall-eyed stereo view of TGase-1 model

The 18 arginine residues, mutations of which have been associated with ARCI, are shown as ball-and-stick. All arginine residues shown in the two beta-barrel domains as well as R142 and R143 of the beta-sandwich domain, are located at domain boundaries. To indicate the active site, C377 is also shown as ball-and-stick (to the left of R286). The protein main chain is colored by domain: beta-sandwich (red), catalytic core (yellow), beta-barrel 1 (green), and beta-barrel 2 (cyan). Figures 3, 4, and 5 were prepared with the programs MOLSCRIPT [Kraulis, 1991] and Raster3D [Merritt and Bacon, 1997].

Figure 4. Arginine residues located at domain interfaces in TGase-1 model

a) The arginines are shown as space-filling, and nearby acidic residues are shown as sticks. The protein main chain is colored by domain: beta-sandwich (orange), catalytic core (yellow), beta-barrel 1 (green), and beta-barrel 2 (cyan). b) Interface between the beta-sandwich and catalytic-core domains of TGase-1, colored by the sequence identity between the model and the template structure (red where identical, blue where different). The amino-acid composition of this interface is highly conserved between model and template. Six residues found mutated in patients with ARCI are indicated with spheres.

Figure 5. Wall-eyed stereo view of the catalytic triad and neighboring residues in TGase-1 model

Side chains are shown as ball-and-stick, with the catalytic residues (Cys 377, His 436, and Asp 459) denoted with darker carbon atoms. Residues associated with missense mutations observed in ARCI patients and the catalytic residues are labeled. For clarity, the side chains of Trp 378, Phe 380, and Ala 381 are not shown. The protein backbone (alpha-carbon trace) is colored according to the sequence identity between the TGase-1 model and coagulation factor XIII template (red where identical, blue where different).