Alternative titles; symbols
HGNC Approved Gene Symbol: TGM3
Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:2,296,001-2,341,079 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p13 | ?Uncombable hair syndrome 2 | 617251 | Autosomal recessive | 3 |
Transglutaminases (protein-glutamine:amine gamma-glutamyltransferases; EC 2.3.2.13) catalyze the formation of lysine isodipeptide crosslinks in proteins between the gamma-amide of a donor glutamine and the epsilon-NH2 of an acceptor lysine. The result is a stable, insoluble macromolecular structure, a process used widely throughout the plant and animal kingdoms. The human haploid genome contains at least 5 distinct transglutaminases that are differentially expressed in time-space and tissue-specific ways. These include the catalytic subunit of factor XIII (134570); band 4.2 (177070), an inactive enzyme that forms a part of the subplasma membrane of erythrocytic and other cells; transglutaminase-1 (TGM1; 190195), a membrane-associated enzyme present in many epithelial as well as some nonepithelial tissues; a ubiquitously expressed tissue transglutaminase-2 (TGM2; 190196); and a proenzyme activity, transglutaminase-3, found in terminally differentiating epidermal and hair keratinocytes. This proenzyme requires activation by proteolysis. The TGM1 and TGM3 enzymes are thought to be involved in the formation of the cornified cell envelope (CE) of the epidermis, hair follicle, and perhaps other stratified squamous epithelia by cross-linking of CE protein constituents with isodipeptide bonds (Kim et al., 1993).
Using a combination of primer extension and PCR with degenerate oligonucleotide primers based on the partial protein sequence of guinea pig TGase3, Kim et al. (1993) isolated partial TGase3 cDNAs from newborn mouse and human foreskin epidermis. The authors used a combination of techniques to clone additional cDNAs corresponding to the entire coding regions of both human and mouse TGase3. The predicted proteins contain 692 amino acids and are 75% identical. Most of the sequence variation occurs in the vicinity of the proteolytic activation site, which lies at the most flexible and hydrophilic region of the molecule. Kim et al. (1993) suggested that cleavage of this exposed flexible hinge region promotes a conformational change in the protein to a more compact form, resulting in activation of the enzyme. Northern blot analysis revealed that the 2.9-kb TGase3 mRNA is expressed in human foreskin and in mouse epidermis and hair follicles. TGase3 expression in mammalian cells was regulated by calcium, as with other late epidermal differentiation products such as loricrin (152445) and profilaggrin (135940), suggesting to the authors that TGase3 is responsible for the later stages of cell envelope formation in the epidermis and hair follicle.
Kim et al. (1993) found that, when expressed in yeast cells, human TGase3 exhibited significant transglutaminase activity.
Using ELISA, Sardy et al. (2002) found that sera from both celiac disease (CD; 212750) and dermatitis herpetiformis (DH; 601230) reacted with TGM2 and TGM3, but the DH antibodies had a markedly higher avidity for TGM3. Immunofluorescence and confocal microscopy demonstrated that IgA precipitates in the papillary dermis of DH patients contained TGM3, but not TGM1 or TGM2. Sardy et al. (2002) concluded that TGM3 is the dominant autoantigen in DH, explaining why skin symptoms rather than intestinal symptoms appear in a proportion of patients with gluten-sensitive disease.
Kim et al. (1994) demonstrated that TGM3 is encoded by a gene of 42.8 kb containing 13 exons. Kim et al. (1994) compared the exon/intron organization with that of the other transglutaminase genes and suggested on this basis and on the basis of sequence homologies that TGM2 and TGM3 belong to a branch of a phylogenetic tree distinct from other transglutaminases.
Using Southern blot hybridization or species-specific PCR amplification of DNAs isolated from a panel of human/rodent somatic cell hybrids, followed by fluorescence in situ hybridization, Wang et al. (1994) mapped the TGM2 and TGM3 genes to chromosome 20q11.2. They stated that on FISH the signal showed overlap into band 20q12. However, Hartz (2011) mapped the TGM3 gene to chromosome 20p13 based on an alignment of the TGM3 sequence (GenBank BC109076) with the genomic sequence (GRCh37).
By whole-exome sequencing in a Turkish patient with uncombable hair syndrome (UHS2; 617251) reported by Kilic et al. (2013), who did not have a mutation in the PADI3 gene (606755), U. Basmanav et al. (2016) identified a homozygous nonsense mutation (Q451X; 600238.0001) in the TGM3 gene. Functional studies in HaCaT and HEK293T cells showed that the mutation led to reduced enzymatic activity.
By whole-exome sequencing in a Turkish patient with uncombable hair syndrome (UHS2; 617251) reported by Kilic et al. (2013), who did not have a mutation in the PADI3 gene (606755), U. Basmanav et al. (2016) identified a homozygous c.1351C-T transition (rs779702016) in the TGM3 gene, resulting in a nonsense mutation (Q451X; 600238.0001). Transient transfection experiments in HaCaT and HEK293T cells showed that wildtype TGM3 led to translation of a protein of about 70 kD, whereas the nonsense mutation resulted in a truncated protein of about 40 kD with a lower detection level. Immunofluorescence analysis showed that TGM3 is located in the cytoplasm and that the truncated form is present in a dramatically lower number of cells. A transglutaminase activity assay with HEK293T cell lysates revealed that wildtype TGM3 had a significantly higher transglutaminase activity in comparison to the truncated protein. No homozygous loss-of-function Q451X mutation was found in the ExAC database.
Hartz, P. A. Personal Communication. Baltimore, Md. 4/20/2011.
Kilic, A., Oguz, D., Can, A., Akil, H., Gurbuz Koz, O. A case of uncombable hair syndrome: light microscopy, trichoscopy and scanning electron microscopy. Acta Dermatovenerol. Croat. 21: 209-211, 2013. [PubMed: 24183230]
Kim, I.-G., Gorman, J. J., Park, S.-C., Chung, S.-I., Steinert, P. M. The deduced sequence of the novel protransglutaminase E (TGase3) of human and mouse. J. Biol. Chem. 268: 12682-12690, 1993. [PubMed: 8099584]
Kim, I.-G., Lee, S.-C., Lee, J.-H., Yang, J.-M., Chung, S.-I., Steinert, P. M. Structure and organization of the human transglutaminase 3 gene: evolutionary relationship to the transglutaminase family. J. Invest. Derm. 103: 137-142, 1994. [PubMed: 7913719] [Full Text: https://doi.org/10.1111/1523-1747.ep12392470]
Sardy, M., Karpati, S., Merkl, B., Paulsson, M., Smyth, N. Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J. Exp. Med. 195: 747-757, 2002. [PubMed: 11901200] [Full Text: https://doi.org/10.1084/jem.20011299]
U. Basmanav, F. B., Cau, L., Tafazzoli, A., Mechin, M.-C., Wolf, S., Romano, M. T., Valentin, F., Wiegmann, H., Huchenq, A., Kandil, R., Bartels, N. G., Kilic, A., and 25 others. Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome. Am. J. Hum. Genet. 99: 1292-1304, 2016. [PubMed: 27866708] [Full Text: https://doi.org/10.1016/j.ajhg.2016.10.004]
Wang, M., Kim, I.-G., Steinert, P. M., McBride, O. W. Assignment of the human transglutaminase 2 (TGM2) and transglutaminase 3 (TGM3) genes to chromosome 20q11.2. Genomics 23: 721-722, 1994. [PubMed: 7851911] [Full Text: https://doi.org/10.1006/geno.1994.1571]