ORPHA: 1775; DO: 0070019;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p13.1 | Dyskeratosis congenita, autosomal recessive 3 | 613988 | Autosomal recessive | 3 | WRAP53 | 612661 |
A number sign (#) is used with this entry because autosomal recessive dyskeratosis congenita-3 (DKCB3) is caused by compound heterozygous mutation in the TCAB1 gene (WRAP53; 612661) on chromosome 17p13.
Dyskeratosis congenita is a genetic disorder of defective tissue maintenance, impaired stem cell function, and cancer predisposition caused by short telomeres resulting from a defect in telomerase. Clinical manifestations may be seen in the skin as leukoplakia, nail dystrophy, and reticular pigmentation, in the bone marrow as pancytopenia, and in the lung as pulmonary fibrosis, as well as in other tissues (summary by Zhong et al., 2011).
For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).
Zhong et al. (2011) reported 2 unrelated patients with the classic triad of DKC, including oral leukoplakia, abnormal skin pigmentation, and nail dystrophy. Both also had bone marrow failure and telomere lengths shorter than the lowest first percentile of controls. One patient developed squamous cell carcinoma of the tongue. Neither had a family history of the disorder.
Dyskeratosis congenita caused by WRAP53 mutations is an autosomal recessive disorder (Zhong et al., 2011).
Batista et al. (2011) showed that even in the undifferentiated state, induced pluripotent stem cells (iPSCs) from dyskeratosis congenita patients harbor the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT (187270), the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1; 300126) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1, telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, since telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. Their findings in iPSCs from dyskeratosis congenita patients led Batista et al. (2011) to conclude that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell culture-based system for the development of targeted therapeutics.
In 2 unrelated patients with DKC, Zhong et al. (2011) identified compound heterozygous mutations in the WRAP53 gene (612661.0001-612661.0004). 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 proteins impaired normal telomerase trafficking, leading to a loss of telomerase complex components, including WRAP53, dyskerin (DKC1; 300126), and TERC (602322) 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.
Batista, L. F. Z., Pech, M. F., Zhong, F. L., Nguyen, H. N., Xie, K. T., Zaug, A. J., Crary, S. M., Choi, J., Sebastiano, V., Cherry, A., Giri, N., Wernig, M., Alter, B. P., Cech, T. R., Savage, S. A., Pera, R. A. R., Artandi, S. E. Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474: 399-402, 2011. [PubMed: 21602826] [Full Text: https://doi.org/10.1038/nature10084]
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]