Alternative titles; symbols
HGNC Approved Gene Symbol: TGM1
Cytogenetic location: 14q12 Genomic coordinates (GRCh38): 14:24,249,114-24,263,177 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q12 | Ichthyosis, congenital, autosomal recessive 1 | 242300 | Autosomal recessive | 3 |
The TGM1 gene encodes transglutaminase-1, a catalytic membrane-bound enzyme that functions in the formation of the epidermal cornified cell envelope, which acts as a mechanical barrier to protect against water loss and infectious agents (Farasat et al., 2009).
Phillips et al. (1990) determined the nucleotide and deduced amino acid sequences of the coding regions of the human and rat keratinocyte transglutaminase (protein-glutamine:amine gamma-glutamyltransferase; EC 2.3.2.13). The human and rat proteins have a molecular mass of about 90 kD and show 92% identity. Substantial similarities were demonstrated in the human clotting factor XIII catalytic subunit (134570), guinea pig liver tissue transglutaminase, and the human erythrocyte band-4.2 protein (177070). The keratinocyte enzyme is most similar to factor XIII, whereas the band-4.2 protein is most similar to tissue transglutaminase. A salient feature of the keratinocyte transglutaminase is its 105-residue extension beyond the N terminus of the tissue transglutaminase. This extension and the unrelated activation peptide of factor XIII (a 37-residue extension) appeared to have been added for specialized functions after divergence of the tissue transglutaminase from their common lineage. Kim et al. (1991) identified mRNAs for all 3 types of transglutaminase (C, K, and E) and sequenced completely the cDNA clones encoding the transglutaminase K enzyme. The deduced 813-amino acid sequence of the TGK protein shares 49 to 53% homology with other transglutaminase proteins of known sequence.
Kim et al. (1992) demonstrated 2 variant forms of the TGM1 gene, the rarer of which contains a 2-nucleotide deletion near the 5-prime end, uses an alternate initiation codon, and differs from the common larger variant only in the first 15 amino acids. Furthermore, they showed that the DNA sequences of intron 14 possess several tracts of dinucleotide repeats that show wide size polymorphism in the human population.
Polakowska et al. (1992) and Kim et al. (1992) both demonstrated that the TGM1 gene has 15 exons.
Yamanishi et al. (1992) demonstrated that the TGM1 gene spans 14.3 kb. The translation start is located in the second exon. The sizes of exons from 3 to 14 are markedly conserved between the genes for human TGM1 and factor XIIIA, another member of the transglutaminase family.
Polakowska et al. (1992) presented a likely phylogenetic tree for 7 known members of the transglutaminase family based on amino acid sequence similarity. They also presented arguments suggesting that the active enzyme evolved first, and the structural human erythrocyte membrane protein 4.2 (band 4.2) evolved from the type II transglutaminases.
Kim et al. (1992) demonstrated that the positions of the 14 TGM1 introns have been conserved in comparison with the genes encoding 2 other transglutaminase-like activities, although the TGM1 gene has relatively smaller introns. On the other hand, the TGM1 enzyme is the largest known transglutaminase, about 90 kD. Comparisons of sequence identities and homologies indicated that the transglutaminase family of genes arose by duplications and subsequent divergent evolution from a common ancestor and became scattered in the human genome.
By the study of somatic cell hybrids, Polakowska et al. (1991) determined that the TGM1 gene is located on chromosome 14. Kim et al. (1992) confirmed the assignment to chromosome 14 by study of somatic cell hybrids and regionalized the assignment to 14q11.2-q13 by in situ hybridization. By fluorescence in situ hybridization, Yamanishi et al. (1992) mapped the TGM1 gene to 14q11.2.
Van Bokhoven et al. (1996) found that the 3-prime end of the RAB geranylgeranyl transferase alpha subunit gene (RABGGTA; 601905) overlaps the promoter region of the TGM1 gene. Further analysis revealed that the RABGGTA and TGM1 genes are located only 2 kb apart in head-to-tail tandem arrangement. These 2 genes are functionally unrelated.
During terminal differentiation, mammalian epidermal cells acquire a deposit of protein 10 to 20 nm thick on the intracellular surface of the plasma membrane, which is termed the cornified or cross-linked cell envelope (CE). The CE is the most insoluble component of the epidermis due to crosslinking by disulfide bonds as well as by gamma-glutamyl-lysine isodipeptide bonds that are formed by the action of transglutaminases. Three different glutaminase activities have been identified in mammalian epidermis and other stratified squamous epithelial tissues. These include a ubiquitous tissue type II enzyme called transglutaminase C (190196); a keratinocyte type I activity called transglutaminase K, which is present in cultured epidermal keratinocytes; and a so-called epidermal activity, transglutaminase E (600238), which is present in hair follicles and advanced differentiated epidermal cells. Transglutaminase K is membrane-associated, whereas the C and E forms are soluble (Nemes et al., 1999). Transglutaminases are defined as enzymes capable of forming isopeptide bonds by transfer of an amine onto glutaminyl residues of a protein. Nemes et al. (1999) showed that the membrane-bound form of the transglutaminase-1 enzyme can also form ester bonds between specific glutaminyl residues of human involucrin (IVL; 147360) and a synthetic analog of epidermal-specific omega-hydroxyceramides. The formation of a lipid envelope approximately 5-nm thick on the surface of epidermal keratinocytes is an important component of normal barrier function. The lipid envelope consists of omega-hydroxyceramides covalently linked by ester bonds to cornified envelope proteins, most abundantly to involucrin. In general the findings indicated a dual role for transglutaminase-1 in epidermal barrier formation and provided insight into the pathophysiology of lamellar ichthyosis (LI; see 242300) resulting from defects in this enzyme.
Mutations in the TGM1 gene were found as the cause of autosomal recessive congenital ichthyosis (ARCI1; 242300) of the lamellar form by Huber et al. (1995) and by Russell et al. (1995). Huber et al. (1995) were prompted to study TGM1 because of the finding that affected individuals in 3 families exhibited drastically reduced transglutaminase activity; in 2 of the families, expression of TGM1 transcripts was diminished or abnormal and no TGM1 protein was detected. Homozygous or compound heterozygous mutations of the TGM1 gene were identified in all 3 families (see 190195.0001-190195.0005). The results suggested that intact cross-linkage of cornified cell envelopes is required for epidermal tissue homeostasis. Russell et al. (1995) were prompted to seek mutations in the TGM1 gene because of the finding that autosomal recessive lamellar ichthyosis maps to 14q11 and shows complete linkage with TGM1. In affected individuals from 2 unrelated families with the lamellar form of ARCI1, they identified homozygosity for point mutations in 2 adjacent arginine residues, R141H (190195.0006 and R142H 190195.0007). Within the transglutaminase family, these arginines are invariant within a conserved region, distant from the catalytic site of the enzyme.
Laiho et al. (1997) studied ARCI in the Finnish population, in which they expected to find single mutations enriched by founder effect. Surprisingly, 5 different mutations of TGM1 (arg141 to his, 190195.0006; arg142 to cys, 190195.0004; gly217 to ser, 190195.0023; val378 to leu, 190195.0008; and arg395 to leu, 190195.0009) were found in Finnish ARCI patients. TGM1 mutations were identified not only in patients with lamellar ichthyosis but also in patients with nonbullous congenital ichthyosis erythroderma. Moreover, haplotype analysis of the chromosomes carrying the most common mutation, a C-to-T transition resulting in the substitution arg142 to cys, revealed that the same mutation had been introduced twice in the Finnish population. In addition to arg142 to cys, 3 other mutations, in arg141 and arg142, had been described elsewhere in other populations. These findings suggested to Laiho et al. (1997) that this region of TGM1 is more susceptible to mutation. Although the corresponding amino acid sequence is conserved in other transglutaminases, mutations do not always cluster in this region; mutations in coagulation factor XIII, for example, do not. A protein model of the arg142-to-cys mutation suggested disruption or destabilization of the protein. In transfection studies, the closely related transglutaminase F13 protein with the corresponding mutation was shown to be susceptible to degradation in COS cells, also suggestive of the destabilizing effect of the arg142-to-cys mutation in TGM1.
Using microsatellite markers linked to the TGM1 gene, Pigg et al. (1998) studied 43 Norwegian families with autosomal recessive congenital ichthyosis, 36 with the lamellar form and 7 with nonbullous congenital ichthyosiform erythroderma, and found a common haplotype for 2 markers on 74% of disease-associated chromosomes. In 3 individuals homozygous for the common haplotype, 2 with lamellar ichthyosis and 1 with congenital ichthyosiform erythroderma, homozygosity for a splice site mutation in the TGM1 gene was identified (IVS5-2A-G; 190195.0002). Screening of probands from the remaining 40 families revealed the splice site mutation on 61 of 72 alleles associated with lamellar ichthyosis and on 9 of 15 alleles associated with congenital ichthyosiform erythroderma. These findings suggested a single founder mutation for most patients with ARCI in Norway.
In African American twin girls with lamellar ichthyosis that spared the face and flexural surfaces, Tok et al. (1999) identified homozygosity for a missense mutation in the TGM1 gene (R315L; 109195.0033). In a male infant of Italian extraction who had lamellar ichthyosis over his entire integument, they identified compound heterozygosity for mutations in TGM1.
In a Japanese boy with ARCI who displayed nonbullous congenital ichthyosiform erythroderma consisting of fine gray or light brown scales on an erythematous skin, Akiyama et al. (2001) identified compound heterozygosity for a missense mutation and a 1-bp deletion in the TGM1 gene (190195.0011 and 190195.0012, respectively).
Cserhalmi-Friedman et al. (2001) analyzed the TGM1 gene in 10 ARCI patients with the lamellar form of ichthyosis and identified compound heterozygosity for 14 different mutations in 7 patients (see, e.g., 190195.0014-190195.0020 and 190195.0024-190195.0026).
In a Japanese girl and a Korean boy with similar clinical histories and ichthyosis in a distribution affecting primarily the trunk, Yang et al. (2001) identified compound heterozygosity for mutations in TGM1 (190195.0021, 190195.0022, and 190195.0027).
Raghunath et al. (2003) described 2 sibs with ARCI who presented the self-healing collodion baby phenotype; they had markedly diminished TGM1 epidermal activity and were found to be compound heterozygous for missense mutations in the TGM1 gene (190195.0013 and 190195.0014). Molecular modeling and biochemical assays of mutant proteins under elevated hydrostatic pressure suggested significantly reduced activity in G278R and a chelation of water molecules in D490G that locked the mutated enzyme in an inactive trans conformation in utero. After birth, these water molecules were removed and the enzyme was predicted to isomerize back to a partially active cis form, explaining the dramatic improvement of this skin condition.
Oji et al. (2006) sequenced the TGM1 gene in 10 ARCI probands from Germany, France, Turkey, the Netherlands, or Morocco, who were primarily affected in a 'bathing suit' distribution, and identified homozygosity or compound heterozygosity for TGM1 mutations in all patients (see, e.g., 190195.0002, 190195.0007, and 190195.0029-190195.0032). Oji et al. (2006) observed that most bathing suit ichthyosis (BSI) mutations are located in exons 5 and 6, leading to an amino acid change in the first part of the catalytic core domain. Digital thermography in healthy individuals showed a striking correlation between warmer body sites and the 'bathing suit' distribution of scaling, and in situ TGase testing in the skin of BSI patients demonstrated a marked decrease of enzyme activity when the temperature was increased from 25 to 37 degrees Celsius. Oji et al. (2006) concluded that the bathing suit form of ichthyosis is caused by TGM1 deficiency and that it is a temperature-sensitive phenotype.
In 8 South African black patients with autosomal recessive congenital ichthyosis in a bathing suit distribution mapping to chromosome 14q11, Arita et al. (2007) sequenced the candidate gene TGM1 and identified homozygosity for a missense mutation (R315L; 190195.0033). Arita et al. (2007) noted that the R315L mutation had been previously identified by Tok et al. (1999) in African-American twins who had a more classic presentation of lamellar ichthyosis in which skin scaling was very extensive, sparing only the face and the flexures.
Aufenvenne et al. (2009) studied 8 of the TGM1 mutations that were identified by Oji et al. (2006) in patients who had ichthyosis in a bathing suit distribution (see, e.g., 190195.0029-190195.0032) as well as 3 mutations associated with classic LI (see, e.g., 190195.0007). Using fluorescence spectrometry, Aufenvenne et al. (2009) demonstrated that both the BSI- and LI-associated mutations had decreased enzyme activity compared to wildtype, but the BSI mutations exhibited a marked shift in temperature optimum from 37 degrees Celsius to 31 degrees Celsius, with residual activity ranging between 13% and 16.5% at the lower temperature, whereas activity at 37 degrees Celsius was less than 10%. The mutations known to cause classic LI showed only activities below 7.5%. Deficient activity of the BSI mutations could be reconstituted by decreasing the temperature to below 33 degrees Celsius. Aufenvenne et al. (2009) concluded that the striking distribution of scaling in BSI is due to mutations that render TGase-1 sensitive to temperatures above 33 degrees Celsius.
Farasat et al. (2009) identified TGM1 mutations in 57 (55%) of 104 patients with autosomal recessive congenital ichthyosis. Twenty-two novel mutations were identified. The presence of a TGM1 mutation was significantly associated with the presence collodion membrane at birth, ectropion, plate-like scales, and alopecia. Patients with at least 1 truncating mutation were more likely to have severe hypohidrosis and overheating at onset of symptoms compared to those with missense mutations. There was a high frequency of mutated arginine codons, most likely due to the deamination of CpG dinucleotides. The most common mutation was an A-to-G transition in intron 5 (190195.0002), which accounted for 28% of the mutated alleles.
In a French family in which 1 sister had a lamellar ichthyosis phenotype and another sister presented a self-healing collodion baby phenotype limited to an acral distribution, Mazereeuw-Hautier et al. (2009) identified compound heterozygosity for 3 different mutations in the TGM1 gene (190195.0034-190195.0036, respectively).
Hackett et al. (2010) reported TGM1 mutations in 5 patients with ARCI who were born with collodion membrane, 3 of whom went on to develop the characteristic bathing suit distribution of ichthyosis (see, e.g., 190195.0033), and 2 of whom developed a self-healing collodion baby (SHCB) phenotype. The authors also reviewed the phenotypes associated with the more than 40 reported mutations in TGM1 and noted that BSI and SHCB mutations appeared to cluster in exons 5, 6, and 7 of the TGM1 gene.
In 16 Spanish ARCI families from Galicia, Rodriguez-Pazos et al. (2011) analyzed 5 ARCI-associated genes and identified TGM1 mutations in 11 probands, all of whom exhibited the lamellar form of ichthyosis. Three mutations accounted for 41%, 23%, and 14% of the TGM1 mutant alleles, respectively (see, e.g., 190195.0038 and 190195.0039). Rodriguez-Pazos et al. (2011) concluded that the high percentage of patients with the same TGM1 mutation, together with the high number of homozygous probands (64%), indicated the existence of a strong founder effect in this population.
Matsuki et al. (1998) generated mice lacking the Tgm1 gene and found that they have erythrodermic skin with abnormal keratinization. In their stratum corneum, degradation of nuclei and keratohyalin F-granules was incomplete and cell envelope assembly was defective. The skin barrier function of Tgm1-null mice was markedly impaired, and these mice died within 4 to 5 hours after birth. These results clearly demonstrate that the Tgm1 gene is essential to the development and maturation of the stratum corneum and to adaptation to the environment after birth. Thus, these knockout mice may be a useful model for severe cases of LI.
Using lamellar ichthyosis as a prototype for therapeutic cutaneous gene delivery, Choate et al. (1996) used the human skin/immunodeficient mouse xenograft model to correct the molecular, histologic, and functional abnormalities of LI patient skin in vivo. They used transglutaminase-1-deficient primary keratinocytes from LI patients combined with high-efficiency transfer of functional transglutaminase enzyme to regenerate engineered human LI epidermis on immunodeficient mice. Engineered LI epidermis displayed normal transglutaminase expression in vivo, unlike unengineered LI epidermis in which transglutaminase activity was absent. Epidermal architecture was also normalized, as was expression of the epidermal differentiation marker filaggrin (135940). Engineered LI skin demonstrated restoration of cutaneous barrier function measures to levels seen in epidermis regenerated by keratinocytes from patients with normal skin, indicating functional correction in vivo of the proposed primary pathophysiologic defect in LI. The results confirmed a major role for transglutaminase in epidermal differentiation and demonstrated a potential future approach to therapeutic gene delivery in human skin.
In a sporadic case of autosomal recessive congenital ichthyosis (ARCI1; 242300) of the lamellar form, Huber et al. (1995) used SSCP and sequence analysis of PCR products to demonstrate a homozygous deletion of a T at position 4640 in exon 8 of the TGM1 gene. This change led to a frameshift and a truncated protein of 442 amino acids that still contained the active site but not the putative Ca(2+)-binding region. Mutation strongly reduced the level of normal transcripts (detectable only by RT-PCR) as reported for nonsense and frameshift mutations in other genes. (The deletion occurred at the first nucleotide of codon 433, TGG, leading to a premature stop codon downstream.)
In a sibship in which 2 sisters had autosomal recessive lamellar ichthyosis (ARCI1; 242300), Huber et al. (1995) demonstrated homozygosity for an A-to-G transition at nucleotide 3366 that converted the canonical splice acceptor sequence from AG to GG. The cDNA products showed the same A-to-G change found in genomic DNA and contained the complete intron 5 sequence inserted into the normal transcript. This inclusion of intron 5 led to a frameshift and created a premature stop codon upstream of the sequences coding for the active site of the TGM1 enzyme.
Pigg et al. (1998) studied 36 Norwegian families with lamellar ichthyosis and 7 with nonbullous congenital ichthyosiform erythroderma (ARCI1), using microsatellite markers linked to the TGM1 gene. One common haplotype for 2 markers was found on 74% of disease-associated chromosomes. Three individuals homozygous for the common haplotype, 2 affected by lamellar ichthyosis and 1 affected by congenital ichthyosiform erythroderma, were analyzed for mutations in the TGM1 gene. All 3 patients were found to be homozygous for an A-to-G transition located in the canonical splice acceptor site of intron 5. Probands from the remaining 40 families were screened for this mutation; the A-to-G transition was found on 61 of 72 alleles associated with lamellar ichthyosis and on 9 of 15 alleles associated with congenital ichthyosiform erythroderma. These findings suggested a single founder mutation for most patients with these 2 phenotypes in Norway. The mutation, which Pigg et al. (1998) designated 2562A-G, resulted in the insertion of a guanosine at position 877 (876insG) in the mature cDNA and the frameshift created a premature termination at codon 293. The mutation was previously observed in 1 family (Huber et al., 1995) with a resulting cDNA that included the entire intron 5, whereas in the Norwegian patients, intron 5 was spliced but with only 1 intronic nucleotide retained, suggesting that the mutation can result in variant transcripts in different individuals.
Shevchenko et al. (2000) presented results from 5 families with the intron 5/exon 6 splice acceptor site mutation. Affected members of 2 families were homozygous for the mutation, and those of the other families were compound heterozygotes. Despite the diverse background of these American patients, haplotype construction identified a common founder chromosome spanning approximately 1.5 cM on 14q11. This haplotype shared many of the alleles of the Norwegian haplotype, though none of the patients claimed Norwegian ancestry. Genealogic information from this ethnically and racially diverse group of patients provided evidence that the founder chromosome may have arisen in the Westphalia region of Germany. No association with congenital ichthyosiform erythroderma was found in their study. Those patients who were homozygous for the acceptor site mutation were less severely affected than many of the compound heterozygotes. Shevchenko et al. (2000) estimated that the IVS5-2A-G mutation originated in Germany and was introduced in the Norwegian population around 1000 to 1100 A.D. They also hypothesized that German families from Westphalia immigrating to the United States introduced this mutation to the North American population.
This mutation in the Norwegian families was reported by Pigg et al. (1998) to result in an insertion of a G in the resultant mRNA (876insG). In the Swiss family reported by Huber et al. (1995), the same A-to-G substitution resulted in an mRNA product that retained the complete intron 5 sequence in the normal transcript. In contrast, Shevchenko et al. (2000) found that mRNA from their patients consisted of 2 transcripts: one with intron 5 inserted at the exon 5 splice represented approximately 90% of the transcripts, whereas the other mRNA fragment with the inserted G represented the remaining 10%. Failure of the spliceosome to excise intron 5 was consistent with the loss of the canonical AG sequence caused by the splice acceptor mutation. Shevchenko et al. (2000) proposed a mechanism for the formation of the extra-G transcript.
Farasat et al. (2009) identified the IVS5-2A-G mutation in 28% of mutated TGM1 alleles from 57 American patients with LI, making it the most common mutation in their study.
In a 16-year-old German boy with ARCI and his similarly affected brother, who both showed a bathing suit distribution in infancy but later displayed mild generalized ichthyosis, Oji et al. (2006) identified compound heterozygosity for what they designated an 877-2A-G splice site mutation in the TGM1 gene, and a 943C-T transition in exon 6, resulting in an arg315-to-cys (R315C; 190195.0031) substitution in the first part of the catalytic core domain. Their unaffected parents were each heterozygous for one of the mutations, neither of which was found in 100 control chromosomes. Analysis of TGase-1 activity in cryosections of patient skin was reduced in healthy skin areas and abnormal in affected skin areas, showing only cytoplasmic and clearly reduced TGase activity. The splice site mutation was also found in compound heterozygosity with 2 distinct TGM1 missense mutations in a 2-year-old German boy with bathing suit ichthyosis and an unrelated 1-year-old German boy who had mild scaling, primarily in the axillae and on the neck.
In 2 sisters with autosomal recessive congenital ichthyosis-1 (ARCI1; 242300) of the lamellar form, Huber et al. (1995) identified 3 mutations in the TGM1 gene, 2 of which were inherited from their father, including a 950C-A transversion in exon 3, resulting in a ser42-to-tyr (S42Y) substitution at a putative phosphorylation site located 5 amino acids upstream of the cys cluster thought to be the membrane anchor region of transglutaminase, and a 1399C-T transition in exon 3, resulting in an arg142-to-cys (R142C; 190195.0004) substitution at a highly conserved residue. The third mutation, inherited from their mother, was a 3549G-A transition in exon 6 of the TGM1 gene, resulting in an arg323-to-gln (R323Q; 190195.0005) substitution at a highly conserved residue. None of the mutations were found in 50 controls. Because mutation analysis had shown that regions adjacent to the cys cluster are important for membrane attachment of the enzyme protein, Huber et al. (1995) suggested that the S42Y mutation might explain the increased ratio of cytosolic to membrane transglutaminase activity and protein observed in the 2 sisters.
For discussion of the arg142-to-cys (R142C) mutation in the TGM1 gene that was found in compound heterozygous state in patients with autosomal recessive congenital ichthyosis-1 (ARCI1; 242300) by Huber et al. (1995), see 190195.0003.
Laiho et al. (1997) analyzed the TGM1 gene in Finnish patients with lamellar ichthyosis and identified homozygosity for R142C in affected members of 2 families. Compound heterozygosity for R142C and another mutation in TGM1 was found in another 9 patients from 6 families, some presenting with lamellar ichthyosis and others exhibiting nonbullous congenital ichthyosiform erythroderma (see, e.g., 190195.0006 and 190195.0008).
For discussion of the arg323-to-gln (R323Q) mutation in the TGM1 gene that was found in compound heterozygous state in patients with autosomal recessive congenital ichthyosis-1 (ARCI1; 242300) by Huber et al. (1995), see 190195.0003.
In 2 affected sibs from a US Caucasian family with severe autosomal recessive congenital ichthyosis (ARCI1; 242300) of the lamellar form, Russell et al. (1995) identified homozygosity for a 1489G-A transition in exon 3 of the TGM1 gene, resulting in an arg141-to-his (R141H) substitution at a highly conserved residue. The mutation was present in heterozygosity in the unaffected parents, who were not known to be related; however, close questioning revealed a common ancestor 6 generations back. The mutation was not found in 104 US Caucasian control alleles.
In a 1-year-old Finnish boy with nonbullous congenital ichthyosiform erythroderma, Laiho et al. (1997) identified compound heterozygosity for R141H and R142C (190195.0004). The authors also identified the R141H mutation in compound heterozygosity with V378L (190195.0008) in an 11-year-old Finnish boy with lamellar ichthyosis.
In 2 affected cousins from a consanguineous Egyptian family with severe autosomal recessive congenital ichthyosis (ARCI1; 242300) of the lamellar form, Russell et al. (1995) identified homozygosity for a 1492G-A transition in exon 3 of the TGM1 gene, resulting in an arg142-to-his (R142H) substitution at a highly conserved residue. The mutation was present in heterozygosity in the unaffected parents, but was not found in 102 Egyptian control alleles.
In a 35-year-old Dutch woman with ARCI in a bathing suit distribution, Oji et al. (2006) identified compound heterozygosity for the R142H mutation and a 376C-T transition in exon 3 of the TGM1 gene, resulting in an arg126-to-cys (R126C; 190195.0030) substitution at a residue at the beginning of the beta-sandwich domain. Her unaffected parents were each heterozygous for one of the mutations, neither of which was found in 100 control chromosomes. In situ TGase testing of an unaffected area of the patient's skin demonstrated a marked decrease in enzyme activity when the temperature was increased from 25 to 37 degrees Celsius. Oji et al. (2006) concluded that the bathing suit distribution of ichthyosis represents a temperature-sensitive phenotype.
In a 25-year-old Finnish woman with autosomal recessive congenital ichthyosis (ARCI1; 242300) manifesting as nonbullous congenital ichthyosiform erythroderma, Laiho et al. (1997) identified compound heterozygosity for a val378-to-leu (V378L) mutation in the TGM1 gene and an unknown allele. The ichthyosis was accentuated in the palms and soles and flexures and was associated with alopecia and ectropion. In a 10-year-old Finnish boy and an unrelated 11-year-old Finnish boy with the lamellar form of ichthyosis, Laiho et al. (1997) identified compound heterozygosity for the V378L mutation and an R395L mutation (190195.0009) or an R141H mutation (190195.0006), respectively.
In 2 Finnish brothers with autosomal recessive congenital ichthyosis (ARCI1; 242300) manifesting as nonbullous congenital ichthyosiform erythroderma, Laiho et al. (1997) identified an arg395-to-leu (R395L) mutation in the TGM1 gene in compound heterozygous state with a second unknown allele. In a 17-year-old Finnish female and a 10-year-old Finnish boy, both with the lamellar form of ichthyosis, they identified the same R395L mutation in compound heterozygosity with G217S (190195.0023) or V378L (190195.0008), respectively.
In a 4-year-old girl with autosomal recessive congenital ichthyosis in a 'bathing suit' distribution (ARCI1; 242300), Petit et al. (1997) identified homozygosity for a 1144G-A transition in exon 7 of the TGM1 gene, resulting in a val382-to-met (V382M) substitution at an evolutionarily conserved residue in the core domain. The mutation was present in heterozygosity in the unaffected parents and an unaffected brother, but was not found in 50 unrelated controls. The patient had large brown scales on the trunk, neck, and scalp, with sparing of the face and limbs. Functional analysis of cultured keratinocytes demonstrated a profound reduction of membrane-bound as well as cytosolic transglutaminase (TG) activity in both affected and unaffected skin from the patient compared to controls. Immunoblot analysis of cytoplasmic and membrane keratinocyte extracts revealed no detectable TGK protein in affected or unaffected skin from the patient, although Northern blot analysis showed TGM1 mRNA of normal size and comparable amounts with an age-matched control. Petit et al. (1997) proposed that other mechanisms may compensate for TGK deficiency in unaffected skin, and suggested that the regulation of the formation of the cornified envelope might differ between these different areas of skin.
Akiyama et al. (2001) reported novel mutations in the TGM1 gene in a Japanese boy with autosomal recessive congenital ichthyosis (ARCI1; 242300). The patient displayed nonbullous congenital ichthyosiform erythroderma, with fine gray or light brown scales on an erythematous skin. An in situ transglutaminase activity assay detected markedly reduced transglutaminase activity in the patient's epidermis. Electron microscopy revealed incomplete thickening of the cornified cell envelope during keratinization in the epidermis. Sequencing of the entire exons and exon-intron borders of TGM1 revealed that the proband was a compound heterozygote for 2 novel mutations, 9008delA (190195.0012) and arg388 to his (R388H). The missense mutation R388H, resulting from a G-to-A transition in exon 8 of the TGM1 gene, altered a conserved residue in the center of the core domain of the protein. The frameshift mutation 9008delA, resulting in a premature termination codon at the tail of the TGM1 peptide, was in the beta-barrel 2 domain (C-terminal end domain) of the peptide, far from the active sites of the TGM1 molecule.
For discussion of the 1-bp deletion in the TGM1 gene (9008delA) that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Akiyama et al. (2001), see 190195.0011.
In 2 sibs with autosomal recessive congenital ichthyosis (ARCI1; 242300) who presented the self-healing collodion baby phenotype and had markedly diminished TGM1 epidermal activity, Raghunath et al. (2003) identified compound heterozygosity for missense mutations in the TGM1 gene: G278R (190195.0014) and D490G. The amino acid substitutions arose from a G-to-A transition at nucleotide 3400 and an A-to-G transition at nucleotide 7367, respectively. Molecular modeling and biochemical assays of mutant proteins under elevated hydrostatic pressure suggested significantly reduced activity in G278R and a chelation of water molecules in D490G that locked the mutated enzyme in an inactive trans conformation in utero. After birth, these water molecules were removed and the enzyme was predicted to isomerize back to a partially active cis form, explaining the dramatic improvement of this skin condition.
For discussion of the gly278-to-arg (G278R) mutation in the TGM1 gene that was found in compound heterozygous state in patients with autosomal congenital ichthyosis (ARCI1; 242300) by Raghunath et al. (2003), see 190195.0013.
In a male patient with ARCI1, Cserhalmi-Friedman et al. (2001) identified compound heterozygosity for the G278R mutation and an arg286-to-gln (R286Q; 190195.0017) substitution in the TGM1 gene. The unaffected parents were each heterozygous for one of the mutations, neither of which was found in 50 unrelated controls. On his trunk, the patient had large scales and mild erythema; immunofluorescence microscopy showed interrupted stratum granulosum and stratum corneum staining, which the authors suggested might be due to instability of mutant protein leading to higher sensitivity to degradation.
In a female patient with autosomal recessive congenital ichthyosis (ARCI1; 242300), Cserhalmi-Friedman et al. (2001) identified compound heterozygosity for a gly392-to-asp (G392D) substitution and a 5-bp deletion (1303_1307del5; 190195.0024) in the TGM1 gene. The unaffected parents were each heterozygous for one of the mutations, neither of which was found in 50 unrelated controls. On her trunk, the patient had large scales and moderate erythema; immunofluorescence microscopy showed no detectable staining, confirming the marked reduction in protein level.
In a female patient with autosomal recessive congenital ichthyosis (ARCI1; 242300), Cserhalmi-Friedman et al. (2001) identified compound heterozygosity for an arg142-to-pro (R142P) and a gln582-to-ter (Q582X; 190195.0025) substitution in the TGM1 gene. The unaffected parents were each heterozygous for one of the mutations, neither of which was found in 50 unrelated controls. On her trunk, the patient had large scales and moderate erythema; immunofluorescence microscopy showed no detectable staining, confirming the marked reduction in protein level.
For discussion of the arg286-to-gln (R286Q) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Cserhalmi-Friedman et al. (2001), see 190195.0014.
In a female patient with autosomal recessive congenital ichthyosis (ARCI1; 242300), Cserhalmi-Friedman et al. (2001) identified compound heterozygosity for a val518-to-met (V518M) and a ser160-to-cys (S160C; 190195.0019) substitution in the TGM1 gene. The unaffected parents were each heterozygous for one of the mutations, neither of which was found in 50 unrelated controls. On her trunk, the patient had large scales and moderate erythema; immunofluorescence microscopy showed positive staining in the stratum granulosum and stratum coreum that corresponded to a normal level of protein, but in vitro enzyme activity assay revealed that mutant enzyme function was reduced to 30% of wildtype activity.
For discussion of the ser160-to-cys (S160C) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Cserhalmi-Friedman et al. (2001), see 190195.0018.
In a female patient with autosomal recessive congenital ichthyosis (ARCI1; 242300), Cserhalmi-Friedman et al. (2001) identified compound heterozygosity for a gly94-to-asp (G94D) substitution and a -86C-T transition (190195.0026) in the TGM1 gene. The unaffected parents were each heterozygous for one of the mutations, neither of which was found in 50 unrelated controls. On her trunk, the patient had large scales and mild erythema.
In a Japanese girl and a Korean boy with similar clinical histories and ichthyosis in a distribution primarily affecting the trunk (ARCI1; 242300), Yang et al. (2001) identified compound heterozygosity for an A-C transversion in exon 5 of the TGM1 gene, resulting in an asn288-to-thr (N288T) substitution, and another missense mutation in TGM1. In the Japanese girl, the second mutation was a C-T transition in exon 6, resulting in an arg306-to-trp (R306W; 190195.0022) substitution, whereas in the Korean boy, the second mutation was an A-T transversion in exon 2 of TGM1, resulting in an asp101-to-val (D101V; 190195.0027) substitution. The unaffected parents were each heterozygous for 1 of the mutations, none of which was found in 50 or more controls. Three-dimensional structural prediction analyses revealed that these missense mutations cause misfolding in the central catalytic core domain of the transglutaminase-1 enzyme that would probably result in reduced enzyme activity. Analysis of TGM1 activity in skin samples from the Korean family showed that both cytosolic and membrane-bound forms of the mutant enzymes had reduced activity, which was approximately 50% of wildtype activity in the parents heterozygous for N288T and D101V, respectively, with mutant TGM1 activity ranging from 5% in the membrane to 15% in the cytosol in the compound heterozygous patient.
For discussion of the arg306-to-trp (R306W) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis primarily affecting the trunk (ARCI1; 242300) by Yang et al. (2001), see 190195.0021.
In a 56-year-old Japanese woman with a mild form of lamellar ichthyosis limited to the neck, abdomen, center of the back, and bilateral axillae, Akiyama et al. (2001) identified compound heterozygosity for 2 missense mutations in the TGM1 gene, a 3404C-T transition in exon 6, resulting in an arg306-to-trp (R306W) substitution and a 2582T-A transversion in exon 4, resulting in a leu204-to-gln (L204Q; 190195.0028) substitution. The patient's mother was heterozygous for the R306W mutation; DNA was unavailable from her deceased father. Neither mutation was found in 25 unrelated Japanese controls. Immunofluorescence demonstrated reduced expression of TGM1 in the granular layer of the patient's epidermis, with normal expression of TGM3. Considering the distribution pattern of the skin lesions and the clinical history that the affected areas enlarged in the summer and became smaller in the winter, Akiyama et al. (2001) suggested that increased water content and elevated pH in the stratum corneum might play an important role in formation of lamellar scales in this patient.
For discussion of the gly217-to-ser (G217S) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Laiho et al. (1997), see 190195.0009.
For discussion of the 5-bp deletion in the TGM1 gene (1303_1307del5) that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Cserhalmi-Friedman et al. (2001), see 190195.0015.
For discussion of the gln582-to-ter (Q582X) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Cserhalmi-Friedman et al. (2001), see 190195.0016.
For discussion of the -86C-T transition in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Cserhalmi-Friedman et al. (2001), see 190195.0020.
For discussion of the asp101-to-val (D101V) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Yang et al. (2001), see 190195.0021.
For discussion of the leu204-to-gln (L204Q) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Akiyama et al. (2001), see 190195.0022.
In a 14-year-old Turkish boy with autosomal recessive congenital ichthyosis in a bathing suit distribution (ARCI1; 242300), Oji et al. (2006) identified homozygosity for an 826T-A transversion in exon 5 of the TGM1 gene, resulting in a tyr276-to-asn (Y276N) substitution in the first part of the catalytic core domain. His unaffected first-cousin parents were heterozygous for the mutation, which was not found in 100 control chromosomes. The patient had thick dark scales on the trunk, with sparing of the limbs and face; the scaling was most pronounced in the axillae. Ultrastructural analysis of affected skin revealed groups of single polygonal clefts, the so-called 'cholesterol clefts,' representing remnants of cholesterol crystals within the thickened massive horny layer, whereas healthy skin from his right arm showed a normal diameter of the stratum corneum and completely normal ultrastructure. Immunohistochemical analysis revealed that in the patient's healthy skin, enzyme localization and activity were almost normal, whereas in affected skin, activity was only present in the cytoplasm and was clearly reduced. In situ TGase testing of the patient's healthy skin demonstrated a marked decrease in enzyme activity when the temperature was increased from 25 to 37 degrees Celsius.
Using fluorescence spectrometry, Aufenvenne et al. (2009) demonstrated that the Y276N mutation not only has decreased enzyme activity compared to wildtype but also exhibits a marked shift in temperature optimum from 37 degrees Celsius to 31 degrees Celsius: residual activity was 14.55% at the lower temperature, whereas activity at 37 degrees Celsius was less than 5%, and the deficient activity could be reconstituted by decreasing the temperature to below 33 degrees Celsius. Aufenvenne et al. (2009) concluded that the striking distribution of scaling in bathing suit ichthyosis is due to mutations that render TGase-1 sensitive to temperatures above 33 degrees Celsius.
For discussion of the arg126-to-cys (R126C) mutation in the TGM1 gene that was found in compound heterozygosity in a patient with autosomal recessive congenital ichthyosis in a bathing suit distribution (ARCI1; 242300) by Oji et al. (2006), see 190195.0007.
Using fluorescence spectrometry, Aufenvenne et al. (2009) demonstrated that the R126C mutation not only has decreased enzyme activity compared to wildtype but also exhibits a marked shift in temperature optimum from 37 degrees Celsius to 31 degrees Celsius: residual activity was 13% at the lower temperature, whereas activity at 37 degrees Celsius was less than 7.5%, and the deficient activity could be reconstituted by decreasing the temperature to below 33 degrees Celsius. In contrast, the R142H mutation (190195.0007) consistently showed activity below 5.5% at either temperature. Aufenvenne et al. (2009) concluded that the striking distribution of scaling in BSI is due to mutations that render TGase-1 sensitive to temperatures above 33 degrees Celsius.
For discussion of the arg315-to-cys (R315C) mutation in the TGM1 gene that was found in compound heterozygous state in patients with autosomal recessive congenital ichthyosis in a bathing suit distribution (ARCI1; 242300) by Oji et al. (2006), see 190195.0002.
Using fluorescence spectrometry, Aufenvenne et al. (2009) demonstrated that the R315C mutation not only has decreased enzyme activity compared to wildtype but also exhibits a marked shift in temperature optimum from 37 degrees Celsius to 31 degrees Celsius: residual activity was about 14% at the lower temperature, whereas activity at 37 degrees Celsius was less than 6%, and the deficient activity could be reconstituted by decreasing the temperature to below 33 degrees Celsius. Aufenvenne et al. (2009) concluded that the striking distribution of scaling in BSI is due to mutations that render TGase-1 sensitive to temperatures above 33 degrees Celsius.
In 2 brothers from a consanguineous family of Moroccan origin with autosomal recessive congenital ichthyosis (ARCI1; 242300) in a bathing suit distribution, Oji et al. (2006) identified homozygosity for a 944G-A transition in exon 6 of the TGM1 gene, resulting in an arg315-to-his (R315H) substitution at a residue in the first part of the catalytic core domain. Their unaffected parents were heterozygous for the mutation, which was not found in 100 control chromosomes. The 16-year-old proband had moderate scaling on the trunk as well as on particular areas of the limbs, whereas his brother had less severe scaling with a similar distribution pattern.
Using fluorescence spectrometry, Aufenvenne et al. (2009) demonstrated that the R315H mutation not only has decreased enzyme activity compared to wildtype but also exhibits a marked shift in temperature optimum from 37 degrees Celsius to 31 degrees Celsius: residual activity was about 13.5% at the lower temperature, whereas activity at 37 degrees Celsius was 6.25%, and the deficient activity could be reconstituted by decreasing the temperature to below 33 degrees Celsius. Aufenvenne et al. (2009) concluded that the striking distribution of scaling in bathing suit ichthyosis is due to mutations that render TGase-1 sensitive to temperatures above 33 degrees Celsius.
In monozygotic African American twin girls with autosomal recessive congenital ichthyosis (ARCI1; 242300) involving nearly the entire integument but sparing the face and flexural surfaces, Tok et al. (1999) identified homozygosity for a 1030G-T transversion in exon 6 of the TGM1 gene, resulting in an arg315-to-leu (R315L) substitution at a highly conserved residue within the catalytic core domain.
In 8 South African black patients with ARCI in a bathing suit distribution, 5 of whom had previously been reported by Jacyk (2005), Arita et al. (2007) identified homozygosity for the R315L mutation in the TGM1 gene. Noting that the mutation was detected in all 8 DNA samples and that several of the affected individuals belonged to the Nguni ethnic groups (Zulu, Swazi, and Xhosa), Arita et al. (2007) concluded that it likely represented a founder effect in this population. The mutation was not found in 50 ethnically matched control samples.
In a boy with ARCI in a bathing suit distribution, who was born of a black South African mother and white Irish father, Hackett et al. (2010) identified compound heterozygosity for the R315L mutation and a 1-bp insertion (1331dupA) in exon 9 of the TGM1 gene (190195.0037), causing a frameshift predicted to result in a premature termination codon. The patient had collodion membrane with eclabium and ectropion noted at birth, and in the first months of life developed lamellar scaling involving large dark scales on his trunk with complete sparing of all 4 limbs and the face. Neither mutation was found in 100 control chromosomes.
In a 7-year-old French girl with autosomal recessive congenital ichthyosis (ARCI1; 242300), who was born with a mild and transient acral self-healing collodion baby phenotype, Mazereeuw-Hautier et al. (2009) identified compound heterozygosity for a 1075G-A transition in exon 7 of the TGM1 gene, resulting in a val359-to-met (V359M) substitution, and a 1187G-A transition in exon 8, resulting in an arg396-to-his (R396H; 190195.0035) substitution. Fluorescence spectroscopy demonstrated that the V359M mutation had 12.8% of the activity of wildtype TGM1, whereas activity of R396H was nearly abolished, at 3.3% of wildtype. The proband's 9-year-old sister, who had ARCI of the classic lamellar type, was compound heterozygous for the R396H mutation and a 7-bp deletion in the TGM1 gene (1922delGGCCTGT; 190195.0036), involving the last 5 nucleotides of exon 12 and the consensus GT donor splice site of intron 12, predicted to cause abnormal splicing and causing a frameshift resulting in a premature termination codon 34 amino acids downstream of the deletion. Their unaffected mother was heterozygous for the R396H mutation, and their apparently unaffected father was a compound heterozygote for V359M and the 7-bp deletion; none of the mutations was found in 100 unrelated Caucasian controls. Mazereeuw-Hautier et al. (2009) noted that a transient and mild anomaly of the skin at birth could not be ruled out in the father.
For discussion of the arg396-to-his (R396H) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Mazereeuw-Hautier et al. (2009), see 190195.0034.
For discussion of the 7-bp deletion in the TGM1 gene (1922_1928delGGCCTGT) that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Mazereeuw-Hautier et al. (2009), see 190195.0034.
For discussion of the 1-bp insertion in the TGM1 gene (1331dupA) that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Hackett et al. (2010), see 190195.0033.
In 3 Spanish probands from Galicia with autosomal recessive congenital ichthyosis (ARCI1; 242300) of the lamellar type, Rodriguez-Pazos et al. (2011) identified homozygosity for a 2278C-T transition in exon 15 of the TGM1 gene, resulting in an arg670-to-ter (R670X) substitution in the beta-barrel-2 domain. Another 3 Galician ARCI patients were compound heterozygous for R670X and a 5-bp deletion (1223_1227delACACA; 190195.0039) in exon 8 of the TGM1 gene, and 1 additional patient was homozygous for the 5-bp deletion. The R670X mutation accounted for 41% and the 5-bp deletion for 23% of TGM1 mutant alleles in the Galician population under study. These findings were consistent with a strong founder effect in this population.
For discussion of the 5-bp deletion in the TGM1 gene (1223_1227delACACA) that was found in compound heterozygous state in patients with autosomal recessive congenital ichthyosis (ARCI1; 242300) by Rodriguez-Pazos et al. (2011), see 190195.0038.
Akiyama, M., Takizawa, Y., Kokaji, T., Shimizu, H. Novel mutations of TGM1 in a child with congenital ichthyosiform erythroderma. Brit. J. Derm. 144: 401-407, 2001. [PubMed: 11251583] [Full Text: https://doi.org/10.1046/j.1365-2133.2001.04037.x]
Akiyama, M., Takizawa, Y., Suzuki, Y., Ishiko, A., Matsuo, I., Shimizu, H. Compound heterozygous TGM1 mutations including a novel missense mutation L204Q in a mild form of lamellar ichthyosis. (Letter) J. Invest. Derm. 116: 992-995, 2001. [PubMed: 11407995] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01367.x]
Arita, K., Jacyk, W. K., Wessagowit, V., van Rensburg, E. J., Chaplin, T., Mein, C. A., Akiyama, M., Shimizu, H., Happle, R., McGrath, J. A. The South African 'bathing suit ichthyosis' is a form of lamellar ichthyosis caused by a homozygous missense mutation, p.R315L, in transglutaminase 1. (Letter) J. Invest. Derm. 127: 490-493, 2007. [PubMed: 16977323] [Full Text: https://doi.org/10.1038/sj.jid.5700550]
Aufenvenne, K., Oji, V., Walker, T., Becker-Pauly, C., Hennies, H. C., Stocker, W., Traupe, H. Transglutaminase-1 and bathing suit ichthyosis: molecular analysis of gene/environment interactions. (Letter) J. Invest. Derm. 129: 2068-2071, 2009. [PubMed: 19212342] [Full Text: https://doi.org/10.1038/jid.2009.18]
Choate, K. A., Medalie, D. A., Morgan, J. R., Khavari, P. A. Corrective gene transfer in the human skin disorder lamellar ichthyosis. Nature Med. 2: 1263-1267, 1996. [PubMed: 8898758] [Full Text: https://doi.org/10.1038/nm1196-1263]
Cserhalmi-Friedman, P. B., Milstone, L. M., Christiano, A. M. Diagnosis of autosomal recessive lamellar ichthyosis with mutations in the TGM1 gene. Brit. J. Derm. 144: 726-730, 2001. [PubMed: 11298529] [Full Text: https://doi.org/10.1046/j.1365-2133.2001.04126.x]
Farasat, S., Wei, M.-H., Herman, M., Liewehr, D. J., Steinberg, S. M., Bale, S. J., Fleckman, P., Toro, J. R. Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA. J. Med. Genet. 46: 103-111, 2009. [PubMed: 18948357] [Full Text: https://doi.org/10.1136/jmg.2008.060905]
Hackett, B. C., Fitzgerald, D., Watson, R. M., Hol, F. A., Irvine, A. D. Genotype-phenotype correlations with TGM1: clustering of mutations in the bathing suit ichthyosis and self-healing collodion baby variants of lamellar ichthyosis. Brit. J. Derm. 162: 448-451, 2010. [PubMed: 19863506] [Full Text: https://doi.org/10.1111/j.1365-2133.2009.09537.x]
Huber, M., Rettler, I., Bernasconi, K., Frenk, E., Lavrijsen, S. P. M., Ponec, M., Bon, A., Lautenschlager, S., Schorderet, D. F., Hohl, D. Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science 267: 525-528, 1995. [PubMed: 7824952] [Full Text: https://doi.org/10.1126/science.7824952]
Jacyk, W. K. Bathing-suit ichthyosis: a peculiar phenotype of lamellar ichthyosis in South African blacks. Europ. J. Derm. 15: 433-436, 2005. [PubMed: 16280294]
Kim, H. C., Idler, W. W., Kim, I. G., Han, J. H., Chung, S. I., Steinert, P. M. The complete amino acid sequence of the human transglutaminase K enzyme deduced from the nucleic acid sequences of cDNA clones. J. Biol. Chem. 266: 536-539, 1991. [PubMed: 1670769]
Kim, I.-G., McBride, O. W., Wang, M., Kim, S.-Y., Idler, W. W., Steinert, P. M. Structure and organization of the human transglutaminase 1 gene. J. Biol. Chem. 267: 7710-7717, 1992. [PubMed: 1348508]
Laiho, E., Ignatius, J., Mikkola, H., Yee, V. C., Teller, D. C., Niemi, K.-M., Saarialho-Kere, U., Kere, J., Palotie, A. Transglutaminase 1 mutations in autosomal recessive congenital ichthyosis: private and recurrent mutations in an isolated population. Am. J. Hum. Genet. 61: 529-538, 1997. [PubMed: 9326318] [Full Text: https://doi.org/10.1086/515498]
Laiho, E., Niemi, K.-M., Ignatius, J., Kere, J., Palotie, A., Saarialho-Kere, U. Clinical and morphological correlations for transglutaminase 1 gene mutations in autosomal recessive congenital ichthyosis. Europ. J. Hum. Genet. 7: 625-632, 1999. [PubMed: 10482949] [Full Text: https://doi.org/10.1038/sj.ejhg.5200353]
Matsuki, M., Yamashita, F., Ishida-Yamamoto, A., Yamada, K., Kinoshita, C., Fushiki, S., Ueda, E., Morishima, Y., Tabata, K., Yasuno, H., Hashida, M., Iizuka, H., Ikawa, M., Okabe, M., Kondoh, G., Kinoshita, T., Takeda, J., Yamanishi, K. Defective stratum corneum and early neonatal death in mice lacking the gene for transglutaminase 1 (keratinocyte transglutaminase). Proc. Nat. Acad. Sci. 95: 1044-1049, 1998. [PubMed: 9448282] [Full Text: https://doi.org/10.1073/pnas.95.3.1044]
Mazereeuw-Hautier, J., Aufenvenne, K., Deraison, C., Ahvazi, B., Oji, V., Traupe, H., Hovnanian, A. Acral self-healing collodion baby: report of a new clinical phenotype caused by a novel TGM1 mutation. Brit. J. Derm. 161: 456-463, 2009. [PubMed: 19500103] [Full Text: https://doi.org/10.1111/j.1365-2133.2009.09277.x]
Nemes, Z., Marekov, L. N., Fesus, L., Steinert, P. M. A novel function for transglutaminase 1: attachment of long-chain omega-hydroxyceramides to involucrin by ester bond formation. Proc. Nat. Acad. Sci. 96: 8402-8407, 1999. [PubMed: 10411887] [Full Text: https://doi.org/10.1073/pnas.96.15.8402]
Oji, V., Hautier, J. M., Ahvazi, B., Hausser, I., Aufenvenne, K., Walker, T., Seller, N., Steijlen, P. M., Kuster, W., Hovnanian, A., Hennies, H. C., Traupe, H. Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype. Hum. Molec. Genet. 15: 3083-3097, 2006. [PubMed: 16968736] [Full Text: https://doi.org/10.1093/hmg/ddl249]
Petit, E., Huber, M., Rochat, A., Bodemer, C., Teillac-Hamel, D., Muh, J.-P., Revuz, J., Barrandon, Y., Lathrop, M., de Prost, Y., Hohl, D., Hovnanian, A. Three novel point mutations in the keratinocyte transglutaminase (TGK) gene in lamellar ichthyosis: significance for mutant transcript level, TGK immunodetection and activity. Europ. J. Hum. Genet. 5: 218-228, 1997. [PubMed: 9359043]
Phillips, M. A., Stewart, B. E., Qin, Q., Chakravarty, R., Floyd, E. E., Jetten, A. M., Rice, R. H. Primary structure of keratinocyte transglutaminase. Proc. Nat. Acad. Sci. 87: 9333-9337, 1990. [PubMed: 1979171] [Full Text: https://doi.org/10.1073/pnas.87.23.9333]
Pigg, M., Gedde-Dahl, T., Jr., Cox, D., Hausser, I., Anton-Lamprecht, I., Dahl, N. Strong founder effect for a transglutaminase 1 gene mutation in lamellar ichthyosis and congenital ichthyosiform erythroderma from Norway. Europ. J. Hum. Genet. 6: 589-596, 1998. [PubMed: 9887377] [Full Text: https://doi.org/10.1038/sj.ejhg.5200224]
Polakowska, R. R., Eddy, R. L., Shows, T. B., Goldsmith, L. A. Epidermal type I transglutaminase (TGM1) is assigned to human chromosome 14. Cytogenet. Cell Genet. 56: 105-107, 1991. [PubMed: 1672846] [Full Text: https://doi.org/10.1159/000133060]
Polakowska, R. R., Eickbush, T., Falciano, V., Razvi, F., Goldsmith, L. A. Organization and evolution of the human epidermal keratinocyte transglutaminase I gene. Proc. Nat. Acad. Sci. 89: 4476-4480, 1992. [PubMed: 1350092] [Full Text: https://doi.org/10.1073/pnas.89.10.4476]
Raghunath, M., Hennies, H.-C., Ahvazi, B., Vogel, M., Reis, A., Steinert, P. M., Traupe, H. Self-healing collodion baby: a dynamic phenotype explained by a particular transglutaminase-1 mutation. J. Invest. Derm. 120: 224-228, 2003. [PubMed: 12542526] [Full Text: https://doi.org/10.1046/j.1523-1747.2003.12032.x]
Rodriguez-Pazos, L., Ginarte, M., Fachal, L., Toribio, J., Carracedo, A., Vega, A. Analysis of TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 in autosomal recessive congenital ichthyosis from Galicia (NW Spain): evidence of founder effects. Brit. J. Derm. 165: 906-911, 2011. [PubMed: 21668430] [Full Text: https://doi.org/10.1111/j.1365-2133.2011.10454.x]
Russell, L. J., DiGiovanna, J. J., Rogers, G. R., Steinert, P. M., Hashem, N., Compton, J. G., Bale, S. J. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nature Genet. 9: 279-283, 1995. [PubMed: 7773290] [Full Text: https://doi.org/10.1038/ng0395-279]
Shevchenko, Y. O., Compton, J. G., Toro, J. R., DiGiovanna, J. J., Bale, S. J. Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies. Hum. Genet. 106: 492-499, 2000. [PubMed: 10914678] [Full Text: https://doi.org/10.1007/s004390000284]
Tok, J., Garzon, M. C., Cserhalmi-Friedman, P., Lam, H. M., Spitz, J. L., Christiano, A. M. Identification of mutations in the transglutaminase 1 gene in lamellar ichthyosis. Exp. Derm. 8: 128-133, 1999. [PubMed: 10232404] [Full Text: https://doi.org/10.1111/j.1600-0625.1999.tb00360.x]
van Bokhoven, H., Rawson, R. B., Merkx, G. F. M., Cremers, F. P. M., Seabra, M. C. cDNA cloning and chromosomal localization of the genes encoding the alpha- and beta-subunits of human Rab geranylgeranyl transferase: the 3-prime end of the alpha-subunit gene overlaps with the transglutaminase 1 gene promoter. Genomics 38: 133-140, 1996. [PubMed: 8954794] [Full Text: https://doi.org/10.1006/geno.1996.0608]
Yamanishi, K., Inazawa, J., Liew, F.-M., Nonomura, K., Ariyama, T., Yasuno, H., Abe, T., Doi, H., Hirano, J., Fukushima, S. Structure of the gene for human transglutaminase 1. J. Biol. Chem. 267: 17858-17863, 1992. [PubMed: 1381356]
Yang, J.-M., Ahn, K.-S., Cho, M.-O., Yoneda, K., Lee, C.-H., Lee, J.-H., Lee, E.-S., Candi, E., Melino, G., Ahvazi, B., Steinert, P. M. Novel mutations of the transglutaminase 1 gene in lamellar ichthyosis. J. Invest. Derm. 117: 214-218, 2001. [PubMed: 11511296] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01429.x]