FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2554295536> ?p ?o ?g. }

• W2554295536 abstract "Abstract Abstract 197 Dyskeratosis congenita (DC) is a multisystem disorder characterized by the diagnostic triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia. Patients with DC are at very high risk of bone marrow failure, cancer, pulmonary fibrosis, and other complications. All patients with DC have very short telomeres; approximately 60% have a mutation in one of 6 telomere biology genes (DCK1, TERC, TERT, TINF2, NOP10 or NHP2). Telomerase (TERT) is the reverse transcriptase which, with its RNA component TERC, extends telomeric repeats to offset the telomere shortening that occurs with DNA replication. Mutations in the catalytic core component of TERT (autosomal dominant or recessive) or TERC (autosomal dominant) cause DC and related telomere biology disorders. The function of the telomerase enzyme in vivo requires additional components including dyskerin (DKC1), which is mutated in patients with X-linked recessive DC. Dyskerin binds the H/ACA sequence within TERC and is required for the biogenesis of telomerase, as well as the biogenesis and function of other RNP complexes, including small nucleolar RNAs (snoRNAs) and small Cajal body RNAs (scaRNAs), involved in the modification of ribosomal RNAs and splicing RNAs, respectively. We recently identified TCAB1 (gene names WDR79, WRAP53) as a novel telomerase component through biochemical purification of telomerase complexes. TCAB1 is a WD40-repeat containing protein that binds the CAB box sequence within TERC. It is a constituent of the active telomerase holoenzyme and inhibition of TCAB1 prevents telomerase from localizing to Cajal bodies where RNA-protein complexes are assembled and modified. Since TCAB1 is required for telomerase trafficking, we evaluated mutations in TCAB1 as a potential cause of DC in 16 mutation-negative patients who were participants in the NCI's prospective Inherited Bone Marrow Failure Syndromes (IBMFS) study. Nine patients had classic DC, defined by the diagnostic triad, or the combination of 1 of the triad plus BMF and 2 other DC-related complications, and leukocyte telomeres <1st percentile for age. An additional 7 DC-like patients (lacking the diagnostic triad) with BMF and telomeres <1st percentile were also evaluated. We performed bi-directional sequence analysis of all 10 exons of TCAB1; PCR and sequence analysis were independently repeated 3 times and reviewed by individuals blinded to patient status. Two unrelated patients with classic DC and very short telomeres had different compound heterozygous mutations in TCAB1. Their parents were not consanguineous and had normal telomere lengths. Each healthy parent harbored a single heterozygous mutation in TCAB1 consistent with autosomal recessive inheritance. These mutations were not present in 380 healthy controls. Each of the four disease-associated TCAB1 alleles showed a defect in accumulation and localization within the Cajal body. Mutant TCAB1 alleles were stably expressed in HeLa cells, but showed markedly reduced accumulation in Cajal bodies by immunofluorescence compared with wild-type TCAB1. Analysis of endogenous TCAB1 expression in TCAB1-mutant, EBV-immortalized lymphoblasts similarly showed a marked impairment of TCAB1 accumulation in Cajal bodies. To model the effects of impaired TCAB1 function, we depleted TCAB1 using siRNA in HeLa cells. TCAB1 depletion prevented TERC from localizing in Cajal bodies, and instead caused TERC to accumulate in nucleoli, as judged by RNA fluorescence in situ hybridization for TERC RNA. Analysis of TERC localization in TCAB1-mutant DC patient lymphoblasts similarly showed that TERC aberrantly accumulated in nucleoli, rather than in Cajal bodies (p<0.001). The overall levels of TERT RNA were unaltered in TCAB1-mutant lymphoblasts by Northern blot. Our data show that compound heterozygosity for TCAB1 mutations leads to a marked mislocalization of telomerase and can cause classic DC. Our findings identify telomerase mislocalization as a novel cause of disease and provide a framework for investigating telomerase trafficking in DC and other disease states. Disclosures: No relevant conflicts of interest to declare." @default.
• W2554295536 created "2016-11-30" @default.
• W2554295536 creator A5006363663 @default.
• W2554295536 creator A5008775096 @default.
• W2554295536 creator A5013627205 @default.
• W2554295536 creator A5036663553 @default.
• W2554295536 creator A5045246519 @default.
• W2554295536 creator A5050022499 @default.
• W2554295536 creator A5073510185 @default.
• W2554295536 creator A5083582714 @default.
• W2554295536 date "2010-11-19" @default.
• W2554295536 modified "2023-09-30" @default.
• W2554295536 title "Mutations In TCAB1 Cause Dyskeratosis Congenita" @default.
• W2554295536 doi "https://doi.org/10.1182/blood.v116.21.197.197" @default.
• W2554295536 hasPublicationYear "2010" @default.
• W2554295536 type Work @default.
• W2554295536 sameAs 2554295536 @default.
• W2554295536 citedByCount "0" @default.
• W2554295536 crossrefType "journal-article" @default.
• W2554295536 hasAuthorship W2554295536A5006363663 @default.
• W2554295536 hasAuthorship W2554295536A5008775096 @default.
• W2554295536 hasAuthorship W2554295536A5013627205 @default.
• W2554295536 hasAuthorship W2554295536A5036663553 @default.
• W2554295536 hasAuthorship W2554295536A5045246519 @default.
• W2554295536 hasAuthorship W2554295536A5050022499 @default.
• W2554295536 hasAuthorship W2554295536A5073510185 @default.
• W2554295536 hasAuthorship W2554295536A5083582714 @default.
• W2554295536 hasConcept C104317684 @default.
• W2554295536 hasConcept C11922738 @default.
• W2554295536 hasConcept C125593758 @default.
• W2554295536 hasConcept C153911025 @default.
• W2554295536 hasConcept C177336024 @default.
• W2554295536 hasConcept C179255354 @default.
• W2554295536 hasConcept C194993378 @default.
• W2554295536 hasConcept C2779285011 @default.
• W2554295536 hasConcept C2779419633 @default.
• W2554295536 hasConcept C34558173 @default.
• W2554295536 hasConcept C502942594 @default.
• W2554295536 hasConcept C54355233 @default.
• W2554295536 hasConcept C54458228 @default.
• W2554295536 hasConcept C67705224 @default.
• W2554295536 hasConcept C86803240 @default.
• W2554295536 hasConcept C88478588 @default.
• W2554295536 hasConcept C94581717 @default.
• W2554295536 hasConceptScore W2554295536C104317684 @default.
• W2554295536 hasConceptScore W2554295536C11922738 @default.
• W2554295536 hasConceptScore W2554295536C125593758 @default.
• W2554295536 hasConceptScore W2554295536C153911025 @default.
• W2554295536 hasConceptScore W2554295536C177336024 @default.
• W2554295536 hasConceptScore W2554295536C179255354 @default.
• W2554295536 hasConceptScore W2554295536C194993378 @default.
• W2554295536 hasConceptScore W2554295536C2779285011 @default.
• W2554295536 hasConceptScore W2554295536C2779419633 @default.
• W2554295536 hasConceptScore W2554295536C34558173 @default.
• W2554295536 hasConceptScore W2554295536C502942594 @default.
• W2554295536 hasConceptScore W2554295536C54355233 @default.
• W2554295536 hasConceptScore W2554295536C54458228 @default.
• W2554295536 hasConceptScore W2554295536C67705224 @default.
• W2554295536 hasConceptScore W2554295536C86803240 @default.
• W2554295536 hasConceptScore W2554295536C88478588 @default.
• W2554295536 hasConceptScore W2554295536C94581717 @default.
• W2554295536 hasLocation W25542955361 @default.
• W2554295536 hasOpenAccess W2554295536 @default.
• W2554295536 hasPrimaryLocation W25542955361 @default.
• W2554295536 hasRelatedWork W1964272015 @default.
• W2554295536 hasRelatedWork W1998760884 @default.
• W2554295536 hasRelatedWork W2014414194 @default.
• W2554295536 hasRelatedWork W2033535804 @default.
• W2554295536 hasRelatedWork W2044485780 @default.
• W2554295536 hasRelatedWork W2049665205 @default.
• W2554295536 hasRelatedWork W2058286861 @default.
• W2554295536 hasRelatedWork W2070857389 @default.
• W2554295536 hasRelatedWork W2101901224 @default.
• W2554295536 hasRelatedWork W2118137773 @default.
• W2554295536 hasRelatedWork W2118817654 @default.
• W2554295536 hasRelatedWork W2142003546 @default.
• W2554295536 hasRelatedWork W2152153687 @default.
• W2554295536 hasRelatedWork W2152859536 @default.
• W2554295536 hasRelatedWork W2492528673 @default.
• W2554295536 hasRelatedWork W2525574721 @default.
• W2554295536 hasRelatedWork W2807269428 @default.
• W2554295536 hasRelatedWork W2914387348 @default.
• W2554295536 hasRelatedWork W3035816855 @default.
• W2554295536 hasRelatedWork W3082835910 @default.
• W2554295536 isParatext "false" @default.
• W2554295536 isRetracted "false" @default.
• W2554295536 magId "2554295536" @default.
• W2554295536 workType "article" @default.