Alternative titles; symbols
HGNC Approved Gene Symbol: WRAP53
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38) : 17:7,686,071-7,703,502 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | Dyskeratosis congenita, autosomal recessive 3 | 613988 | Autosomal recessive | 3 |
The WRAP53 gene encodes a protein involved in the trafficking of telomerase (summary by Venteicher et al., 2009).
Venteicher et al. (2009) identified WD repeat-containing protein-79 (WDR79) as a dyskerin (300126)-associated protein and renamed it TCAB1 for 'telomerase Cajal body protein-1.' Immunoprecipitation showed that TCAB1 interacted specifically with dyskerin, TERT (187270), and TERC (602322), all principal components of active telomerase, and with small Cajal body RNAs (scaRNAs), which are involved in modifying splicing RNAs. Immunoprecipitation and immunofluorescence experiments showed that TCAB1 is a holoenzyme subunit that is notably enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. Depletion of TCAB1 by RNA interference prevented TERC from associating with Cajal bodies, disrupted telomerase-telomere association, and abrogated telomere synthesis by telomerase. Thus, Venteicher et al. (2009) concluded that TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells.
Mahmoudi et al. (2009) found that the WRAP53 gene consists of 13 exons including 3 alternative start exons termed 1-alpha, 1-beta, and 1-gamma. Exons 1-alpha and 1-gamma overlap p53 exons 1 and Hp53int1, respectively.
By analysis of sequence databases, Mahmoudi et al. (2009) found that TCAB1 is located on chromosome 17p13 immediately upstream and antisense to p53 (191170); they renamed the gene WRAP53 (WD-encoding RNA antisense to p53).
Zhong et al. (2011) demonstrated that knockdown of WRAP53 in HeLa cells using siRNA resulted in a loss of dyskerin (DKC1; 300126) and TERC from Cajal bodies, although dyskerin still properly localized to nucleoli. These findings indicated that dyskerin accumulates in Cajal bodies through its physical interaction with TCAB1 and/or through tethering to CAB-box-containing RNAs.
In 2 unrelated patients with autosomal recessive dyskeratosis congenita-3 (DKCB3; 613988), Zhong et al. (2011) identified compound heterozygous mutations in the TCAB1 gene (612661.0001-612661.0004). The patients had oral leukoplakia, nail dystrophy, abnormal skin pigmentation, bone marrow failure, and shortened telomeres, and 1 developed squamous cell carcinoma of the tongue. Each unaffected parent was heterozygous for 1 of the mutations. In vitro functional expression studies in HeLa cells and patient cells showed that the mutant WRAP53 protein impaired normal telomerase trafficking, leading to a loss of telomerase complex components, including TCAB1, dyskerin, and TERC from Cajal bodies. The severe telomere shortening observed in patients, together with the overall preserved levels of TERC, showed that the telomerase RNP was impaired in its ability to maintain telomeres due to mislocalization to the nucleolus.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human WRAP53 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient with autosomal recessive dyskeratosis congenita-3 (DKCB3; 613988), Zhong et al. (2011) identified compound heterozygosity for 2 mutations in the WRAP53 gene: a 492C-A transversion in exon 2 resulting in a phe164-to-leu (F164L) substitution, and a 1192C-T transition in exon 8 resulting in an arg398-to-trp (R398W; 612661.0002) substitution. The patient had oral leukoplakia, nail dystrophy, abnormal skin pigmentation, bone marrow failure, and shortened telomeres, and developed squamous cell carcinoma of the tongue. Each unaffected parent was heterozygous for 1 of the mutations. Both mutations occurred in highly conserved residues and were not found in 380 controls. In vitro functional expression studies in HeLa cells and patient cells showed that the mutant WRAP53 protein impaired normal telomerase trafficking, leading to a loss of telomerase complex components, including TCAB1, dyskerin, and TERC from Cajal bodies. The severe telomere shortening observed in patients, together with the overall preserved levels of TERC, showed that the telomerase RNP was impaired in its ability to maintain telomeres due to mislocalization to the nucleolus.
For discussion of the arg398-to-trp (R398W) mutation in the WRAP53 gene that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-3 (DKCB3; 613988) by Zhong et al. (2011), see 612661.0001.
In a patient with autosomal recessive dyskeratosis congenita-3 (DKCB3; 613988), Zhong et al. (2011) identified compound heterozygosity for 2 mutations in the WRAP53 gene: a 1126C-T transition in exon 7 resulting in a his376-to-tyr (H376Y) substitution, and a 1303G-A transition in exon 9 resulting in a gly435-to-arg (G435R; 612661.0004) substitution. The patient had oral leukoplakia, nail dystrophy, abnormal skin pigmentation, bone marrow failure, and shortened telomeres. Each unaffected parent was heterozygous for 1 of the mutations. Both mutations occurred in highly conserved residues and were not found in 380 controls. In vitro functional expression studies in HeLa cells and patient cells showed that the mutant WRAP53 protein impaired normal telomerase trafficking, leading to a loss of telomerase complex components, including TCAB1, dyskerin, and TERC from Cajal bodies. The severe telomere shortening observed in patients, together with the overall preserved levels of TERC, showed that the telomerase RNP was impaired in its ability to maintain telomeres due to mislocalization to the nucleolus.
For discussion of the gly435-to-arg (G435R) mutation in the WRAP53 gene that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-3 (DKCB3; 613988) by Zhong et al. (2011), see 612661.0003.
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Mahmoudi, S., Henriksson, S., Corcoran, M., Mendez-Vidal, C., Wiman, K. G., Farnebo, M. Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage. Molec. Cell 33: 462-471, 2009. Note: Erratum: Molec. Cell 64: 1009 only, 2016. [PubMed: 19250907] [Full Text: https://doi.org/10.1016/j.molcel.2009.01.028]
Venteicher, A. S., Abreu, E. B., Meng, Z., McCann, K. E., Terns, R. M., Veenstra, T. D., Terns, M. P., Artandi, S. E. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323: 644-648, 2009. [PubMed: 19179534] [Full Text: https://doi.org/10.1126/science.1165357]
Zhong, F., Savage, S. A, Shkreli, M., Giri, N., Jessop, L., Myers, T., Chen, R., Alter, B. P., Artandi, S. E. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25: 11-16, 2011. [PubMed: 21205863] [Full Text: https://doi.org/10.1101/gad.2006411]