Transglutaminases, including the product of the TGM1 gene, catalyze formation of epsilon-(gamma-glutamyl)-lysine crosslinks in proteins and stabilize biological structures. In the epidermis, TGM1 is required for the formation of the cross-linked envelope. Point mutations in the TGM1 gene cause deficits in enzyme activity. TGM1 is normally expressed in the suprabasal cells of stratifying epithelia such as epidermis, the upper digestive tract, the female lower genital tract and in the endometrial epithelium late in pregnancy. It is also expressed as a result of squamous metaplasia in the trachea induced by vitamin A deprivation and in a number of epithelial cell types, including those from bladder and endometrium, induced by culture on plastic.
One of two major regions, at -1.5 kb in the distal promoter, contains a consensus AP1 binding site, and the other region, in the proximal promoter at -0.45 kb, contains a CRE-like binding site.
Russell et al. (1994) conducted linkage analysis for the locus for lamellar ichthyosis (LI) in both inbred and outbred families from Egypt and US, respectively. Results indicated that severe LI was linked to several markers within a 9.3-cM region on 14q11. Affected individuals in inbred families were found to have striking homozygosity for markers in this region. The transglutaminase-1 gene (TGM1) maps to the same region and encodes one of the enzymes responsible for crosslinking epidermal proteins during formation of the stratum corneum. The TGM1 locus was completely linked to LI (maximum lod = 9.11). Later, Russell et al. (1995) identified compound heterozygosity for missense mutations in the TGM1 gene in two of these multiplex LI Egyptian families used in the linkage study. Each nucleotide change causes a non-conservative amino acid substitution of histidine for one of two adjacent arginine residues in exon 3 of the TGM1 gene (Arg141His, Arg142His). Within the transglutaminase family, these arginines are invariant within a conserved region, distant from the catalytic site of the enzyme. Russell et al. (1995) hypothesized that these mutations adversely affect formation of crosslinks essential in production of cornified cell envelopes and a normal stratum corneum layer of the skin.
Shawky et al. (2004) investigated forty-three autosomal recessive congenital ichthyosis (ARCI) Egyptian individuals in 16 families with severe lamellar ichthyosis (LI) and 10 families with congenital ichthyosiformis erythroderma (CIE). Shawky et al. (2004) identified 5 alleles in two Egyptian families as having intron-5/exon-6 splice acceptor mutation recognized by the MspI restriction endonuclease. This promoted to a frequency of 9.6% for this mutation (5 splice-mutation alleles/52 alleles tested). Shawky et al. (2004) extended their dataset to update the detection of R142H mutation in 4 CIE Egyptian families and one LI phenotype (frequency of 28.8%; 15/52). However, they did not observe the R141H among the Egyptian population. There was also no correlation between phenotype and genotype in the study. The mutant alleles detected in intron-5 acceptor splice-site were associated with the other extreme of CIE phenotypes rather than the severe LI form.
Wakil et al., (2016) described three unrelated Saudi patients with congenital ichthyosis born to consanguineous parents. Blood samples from all patients and their family members were obtained for sequencing of TGM1. Wakil et al., (2016) identified two novel mutations (p.Tyr136Ter) and (p.Ser326Cysfs*8) in the TGM1 gene in the three different families. Combined approach of homozygousity mapping and direct sequencing analysis was helpful in confirming the diagnosis of these patients.
Bastaki et al. (2017) identified the underlying mutations affecting 5 Emirati congenital ichthyosis patients. Patient 1 was a female child born as a collodion baby to a consanguineous family. She exhibited sparse scalp hair, bilateral ectropion, generalized large thick skin plates with cracks and thin membranes in-between, peeling of skin and eclabium. She was diagnosed with Lamellar Ichthyosis. DNA analysis helped uncover a novel homozygous variant c.1085T>G (p.Leu362Arg) in exon 7 of the patient’s TGM1 gene. The mutation was predicted to affect a highly conserved catalytic core domain of the TGM1 protein. Both parents were found to be heterozygous for the variant.
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