Alternative titles; symbols
HGNC Approved Gene Symbol: DCT
Cytogenetic location: 13q32.1 Genomic coordinates (GRCh38): 13:94,436,811-94,549,406 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q32.1 | Oculocutaneous albinism, type VIII | 619165 | Autosomal recessive | 3 |
Bouchard et al. (1994) isolated a full-length cDNA clone for TYRP2 and demonstrated its expression in melanocytic cells.
Cassady and Sturm (1994) found that the human TYRP2 protein has 83% identity and 90% similarity to the mouse sequence and has all the structural characteristics of the tyrosinase protein family, including a signal peptide, 15 conserved cysteine residues, 2 copper-binding domains, and a C-terminal membrane-spanning region. Northern blot analysis showed that TYRP2 is expressed at high levels in human melanoma cells.
Genetic analyses of coat colors in the mouse resulted in mapping 3 of the classic pigmentation mutations known as 'albino,' 'brown,' and 'slaty' to mouse chromosomes 7 (c locus), 4 (b locus), and 14 (slt locus), respectively. As reviewed by Kwon (1993), the cDNAs encoded by each of these loci have been isolated and characterized to define the tyrosinase-related gene family. The family consists of genes encoding the proteins tyrosinase (TYR; 606933), tyrosinase-related protein-1 (TYRP1; 115501), and tyrosinase-related protein-2 (TYRP2), all enzymes involved in melanin pigment biosynthesis. These genes in the mouse are the sites of the albino, brown, and slaty mutations, respectively.
Jackson et al. (1992) showed that the mouse Tyrp2 gene, which encodes dopachrome-tautomerase activity, is located on chromosome 14 and represents the slaty locus.
By in situ hybridization, Bouchard et al. (1994) assigned the TYRP2 gene to human chromosome 13q32, thus extending a region of homology of synteny with mouse chromosome 14.
Sturm et al. (1994) mapped the human TYRP2 gene to chromosome 13q31-q32 by fluorescence in situ hybridization.
Sturm et al. (1995) showed that the TYRP2 protein is encoded by 8 exons. TYRP1, TYRP2, and the tyrosinase gene all have a C-terminal membrane spanning exon. The position of intron junctions suggested that TYRP1 was derived from a TYR duplication and then was itself duplicated to give rise to the TYRP2 gene. The comparisons also suggested that at least some of the introns within the TYR, TYRP1, and TYRP2 coding regions were gained after duplication and that intron slippage was unlikely to have occurred.
NYESO1 (CTAG; 300156) is expressed on tumor cells of many different types, including melanoma. TRP2 is a melanoma-differentiation antigen. In a melanoma vaccine trial in patients with metastatic disease, Khong and Rosenberg (2002) identified tumor-infiltrating lymphocytes (TILs) that recognized NYESO1, TRP2, and a TRP2 splice variant from a patient who experienced dramatic tumor regression. The TILs expressed immunologic reactivity against these antigens before vaccination with antigens, none of which she had been vaccinated against. Khong and Rosenberg (2002) proposed that NYESO1 and TRP2 may be useful in the active immunotherapy of patients with melanoma.
Sendoel et al. (2010) showed that C. elegans HIF1, homologous to human HIF-alpha (603348), protects against DNA damage-induced germ cell apoptosis by antagonizing the function of CEP1, the homolog of p53 (191170). The antiapoptotic property of HIF1 is mediated by means of transcriptional upregulation of the tyrosinase family member TYR2 in the ASJ sensory neurons. TYR2 is secreted by ASJ sensory neurons to antagonize CEP1-dependent germline apoptosis. Knockdown of the TYR2 homolog TRP2, also called DCT, in human melanoma cells similarly increased apoptosis, indicating an evolutionarily conserved function. Sendoel et al. (2010) concluded that their findings identified a novel link between hypoxia and programmed cell death, and provided a paradigm for HIF1 dictating apoptotic cell fate at a distance.
In a 12-year-old French girl with mild oculocutaneous albinism (OCA8; 619165), Pennamen et al. (2021) identified compound heterozygosity for a missense mutation (C40S; 191275.0001) and a 14-bp deletion (191275.0002) in the DCT gene. In an unrelated 36-year-old North African woman with mild OCA, born of consanguineous parents, they identified homozygosity for a different missense mutation in DCT (C61W; 191275.0003). Observations in mice carrying equivalent missense mutations, as well as in a mouse line with a frameshift deletion in Dct, suggested that the missense variants present in the OCA patients cause partial or complete loss of function of DCT.
In 3 affected members of a consanguineous Turkish family segregating OCA8, Volk et al. (2021) identified a homozygous missense mutation in the DCT gene (G59V; 191275.0004). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Expression studies in HEK293 cells showed that the mutant DCT protein DCT protein had incomplete glycosylation and maturation and was abnormally retained in the endoplasmic reticulum. By Sanger sequencing in an unrelated patient with OCA8, Volk et al. (2021) identified compound heterozygous nonsense mutations (Y292X, 191275.0005 and W469X 191275.0006) in the DCT gene.
Jackson et al. (1992) found an amino acid substitution in Tyrp2, arg194-to-gln, present in slaty mice to be responsible for a significant decrease in dopachrome-tautomerase activity. Budd and Jackson (1995) characterized point mutations in the Tyrp2/Dct gene responsible for the phenotype in 2 slaty mice.
Pennamen et al. (2021) generated mice with missense mutations in the Dct gene that were equivalent to those found in patients with OCA8, C40S (191275.0001) and C61W (191275.0003), as well as mice with a Dct deletion causing a frameshift resulting in a premature stop codon. Heterozygous mice showed normally pigmented black nonagouti fur, whereas all homozygous mice displayed dark gray hair. Colorimetric assays of the dorsal coat along light-dark, blue-yellow, and red-green axes showed significant differences from control mice for all homozygotes in all 3 dimensions. The degree of hypopigmentation with the C61W mutation was indistinguishable from that associated with the null mutation, whereas mice homozygous for C40S were consistently less severely affected. Histologic analysis of eyes from adult Dct -/- mice showed significantly less pigmentation of the retinal pigment epithelium (RPE) than wildtype retinas. The authors also studied zebrafish with knockdown of dct and observed melanophores at 48 hours postfertilization (hpf) that were lighter and wider than those of controls, and eye pigmentation that was slightly lighter. Quantification via whole-embryo melanin assay confirmed an approximately 30% reduction in total melanin in dct-knockdown embryos compared to controls. At 120 hpf, despite a normal pattern of skin melanophores, the intracellular pigmentation of morphants was weaker and showed an abnormal stellate pattern compared to controls, and morphants also showed significant microphthalmia. Histologic analysis of eyes at 48 hpf showed 1 homogeneous layer of neurons in the dct-knockdown embryos rather than the normal stratification of neural retina into inner and outer layers. The RPE was clearly hypopigmented, with disheveled cells and wavy contours, in contrast to the normal heavily pigmented cobblestoned single-cell layer.
In a 12-year-old French girl with mild oculocutaneous albinism (OCA8; 619165), Pennamen et al. (2021) identified compound heterozygosity for a c.118T-A transversion (c.118T-A, NM_001129889.2) in exon 1 of the DCT gene, resulting in a cys40-to-ser (C40S) substitution at a highly conserved cysteine residue in a cys-rich domain within an EGF-like domain, and a 14-bp deletion (c.1406_1419del; 191275.0002) in exon 9 of the DCT gene, causing a frameshift predicted to result in a premature termination codon (Phe469Ter). Her unaffected parents were each heterozygous for 1 of the mutations.
For discussion of the 14-bp deletion (c.1406_1419del, NM_001129889.2) in exon 9 of the DCT gene, causing a frameshift predicted to result in a premature termination codon (Phe469Ter), that was found in compound heterozygous state in a 12-year-old French girl with mild oculocutaneous albinism (OCA8; 619165) by Pennamen et al. (2021), see 191275.0001.
In a 36-year-old woman of North African descent (patient 2) with mild oculocutaneous albinism (OCA8; 619165), Pennamen et al. (2021) identified homozygosity for a c.183C-G transversion (c.183C-G, NM_001129889.2) in exon 1 of the DCT gene, resulting in a cys61-to-trp (C61W) substitution at a highly conserved cysteine residue in a cys-rich domain within an EGF-like domain. DNA was unavailable from her consanguineous parents for segregation analysis.
In 3 members of a consanguineous Turkish family with oculocutaneous albinism (OCA8; 619165), Volk et al. (2021) identified homozygosity for a c.176G-T transversion (c.176G-T, NM_001922.5) in the DCT gene, resulting in a gly59-to-val (G59V) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD and dbSNP databases. Expression studies of DCT with the G59V mutation in HEK293 cells showed that the mutant protein had incomplete glycosylation and maturation. The mutant protein was further shown to be abnormally retained in the endoplasmic reticulum (ER), whereas the wildtype protein was both localized to the ER and to vesicular structures independent of the ER.
In an 18-year-old Caucasian man with oculocutaneous albinism (OCA8; 619165), Volk et al. (2021) identified compound heterozygous nonsense mutations in the DCT gene: a c.876C-A transversion (c.876C-A, NM_001922.5), resulting in a tyr292-to-ter (Y292X) substitution, and a c.1407G-A transition, resulting in a trp469-to-ter (W469X; 191275.0006) substitution. The mutations were identified by Sanger sequencing of the DCT gene. In the gnomAD database, the Y292X and W469 variants were present at allele frequencies of 0.00006136 and 0.00005068, respectively. Functional studies were not performed.
For discussion of the c.1407G-A transition (c.1407G-A, NM_001922.5) in the DCT gene, resulting in a trp469-to-ter (W469X) substitution, that was identified in a patient with oculocutaneous albinism (OCA8; 619165) by Volk et al. (2021), see 191275.0005.
Bouchard, B., Del Marmol, V., Jackson, I. J., Cherif, D., Dubertret, L. Molecular characterization of a human tyrosinase-related-protein-2 cDNA: patterns of expression in melanocytic cells. Europ. J. Biochem. 219: 127-134, 1994. [PubMed: 8306979] [Full Text: https://doi.org/10.1111/j.1432-1033.1994.tb19922.x]
Budd, P. S., Jackson, I. J. Structure of the mouse tyrosinase-related protein-2/dopachrome tautomerase (Tyrp2/Dct) gene and sequence of two novel slaty alleles. Genomics 29: 35-43, 1995. [PubMed: 8530099] [Full Text: https://doi.org/10.1006/geno.1995.1212]
Cassady, J. L., Sturm, R. A. Sequence of the human dopachrome tautomerase-encoding TRP-2 cDNA. Gene 143: 295-298, 1994. [PubMed: 8206391] [Full Text: https://doi.org/10.1016/0378-1119(94)90114-7]
Jackson, I. J., Chambers, D. M., Tsukamoto, K., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Hearing, V. A second tyrosinase-related protein, TRP-2, maps to and is mutated at the mouse slaty locus. EMBO J. 11: 527-535, 1992. [PubMed: 1537334] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05083.x]
Khong, H. T., Rosenberg, S. A. Pre-existing immunity to tyrosinase-related protein (TRP)-2, a new TRP-2 isoform, and the NY-ESO-1 melanoma antigen in a patient with a dramatic response to immunotherapy. J. Immun. 168: 951-956, 2002. [PubMed: 11777994] [Full Text: https://doi.org/10.4049/jimmunol.168.2.951]
Kwon, B. S. Pigmentation genes: the tyrosinase gene family and the pmel 17 gene family. J. Invest. Derm. 100: 134S-140S, 1993. [PubMed: 8432998] [Full Text: https://doi.org/10.1111/1523-1747.ep12465022]
Pennamen, P., Tingaud-Sequeira, A., Gazova, I., Keighren, M., McKie, L., Marlin, S., Gherbi Halem, S., Kaplan, J., Delevoye, C., Lacombe, D., Plaisant, C., Michaud, V., Lasseaux, E., Javerzat, S., Jackson, I., Arveiler, B. Dopachrome tautomerase variants in patients with oculocutaneous albinism. Genet. Med. 23: 479-487, 2021. [PubMed: 33100333] [Full Text: https://doi.org/10.1038/s41436-020-00997-8]
Sendoel, A., Kohler, I., Fellmann, C., Lowe, S. W., Hengartner, M. O. HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature 465: 577-583, 2010. [PubMed: 20520707] [Full Text: https://doi.org/10.1038/nature09141]
Sturm, R. A., Baker, E., Sutherland, G. R. Assignment of the tyrosinase-related protein-2 gene (TYRP2) to human chromosome 13q31-q32 by fluorescence in situ hybridization: extended synteny with mouse chromosome 14. Genomics 21: 293-296, 1994. [PubMed: 8088811] [Full Text: https://doi.org/10.1006/geno.1994.1266]
Sturm, R. A., O'Sullivan B. J., Box, N. F., Smith, A. G., Smit, S. E., Puttick, E. R. J., Parsons, P. G., Dunn, I. S. Chromosomal structure of the human TYRP1 and TYRP2 loci and comparison of the tyrosinase-related protein gene family. Genomics 29: 24-34, 1995. [PubMed: 8530077] [Full Text: https://doi.org/10.1006/geno.1995.1211]
Volk, A. E., Hedergott, A., Preising, M., Rading, S., Fricke, J., Herkenrath, P., Nurnberg, P., Altmuller, J., von Ameln, S., Lorenz, B., Neugebauer, A., Karsak, M., Kubish, C. Biallelic mutations in L-dopachrome tautomerase (DCT) cause infantile nystagmus and oculocutaneous albinism. Hum. Genet. 140: 1157-1168, 2021. [PubMed: 33959807] [Full Text: https://doi.org/10.1007/s00439-021-02285-0]