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 ... 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 ... 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.
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 ... 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.