PHILIP MASON

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..The severe mutations mostly affect residues at the dimer interface or those that interact with a structural NADP molecule that stabilizes the enzyme...

..Here we review several scenarios in which telomerase levels are disturbed, in human diseases or following genetic manipulation in mice...

..Screening for TERC gene mutations is unlikely to diagnose occult DC in children with severe bone marrow failure who require a hematopoietic stem cell transplant...

..However, our results suggest that several generations of TERT haploinsufficiency are needed to produce the very short telomeres seen in patients with DC...

..We considered the possibility that this patient has a defect in telomere function resulting in features of both DC and IMAGe association...

..Hence, our findings show that point mutations in dyskerin may affect both the telomerase and pseudouridylation pathways and the extent to which these functions are altered can vary for different mutations...

..This review highlights recent research on dyskeratosis congenita and its relevance to other fields, including cancer and aging...

..Thus, dyskerin interacts with telomerase and affects telomere maintenance independently of telomere length...

..We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. In the absence of BMF, telomere length measurements should be interpreted with caution...

..Since mice with no telomerase are viable in the first generations the lethality we observe is unlikely to be due to the effects of mutated dyskerin on telomerase activity...

..Expression of RNA and protein was reduced compared to wild type animals, but no abnormalities of growth and development or in blood values were found in mutant mice. Thus Dkc1 mutations have variable expression in mice, as in humans...

..Here we discuss these results in terms of the role of dyskerin in telomere maintenance and the possible role that the DNA damage response plays in the pathogenesis of DC...

..Thus in these families the expression of both TERT alleles and the inherited telomere length contribute to the clinical phenotype...

..The degree of telomere dysfunction is the major determinant of disease onset and manifestations...

..The anomalously migrating RNA is turned over rapidly. Analysis of ribosomal RNA in these cells suggests the altered mobility is due to inefficient pseudouridylation...

..We conclude that hepatocytes can survive without dyskerin but that the role of dyskerin in RNA modification is essential for cellular proliferation...

..The increase in C/D snoRNAs corresponded with an increase in the abundance of the mRNAs transcribed from snoRNA host genes, suggesting the increase may be part of a cellular response to defective ribosome synthesis...

..These findings reveal an unanticipated requirement for additional enzymes in telomerase biogenesis and suggest alternative approaches for inhibiting telomerase in cancer...

..In addition, the distribution of these G6PD variants is more similar to that found in an Italian population than in other Middle Eastern countries...

..Because of the importance of telomerase in tumour formation and aging, study of this disease may provide important clues about these fundamental processes...

..Here we show that disease anticipation is observed in families with this disease and that this is associated with progressive telomere shortening...

..Finally, experiments reconstituting telomerase with both normal and mutant TERC molecules suggest the mutations act via haploinsufficiency rather than by a dominant-negative mechanism...

..Furthermore, we found that the messenger RNA of G6PD(180-182delTCT) is unstable, which may contribute to the severe G6PD deficiency observed in these patients. We propose the name "G6PD Amsterdam" for this new variant...

..Thus, the number of cells with excessively short telomeres and the degree of residual telomerase activity may determine the onset of disease in patients with AD DC...

..This study highlights the considerable genetic and phenotypic diversity of DC...

..This study suggests that the metabolic consequences of a combined deficiency of GPI and G6PD might be responsible for a different clinical outcome than predicted for either defect in isolation...

..We confirmed that the variant 134 had a functional gamma-carboxyglutamic acid (Gla) domain and that EGF1 was correctly folded. This is the first clear evidence that EGF2 is required for the expression of PS activity...

..027). These data indicate that, in a subset of patients with aplastic anaemia, the disorder might be associated with a genetic lesion in the telomere maintenance pathway...

..falciparum restores some of the G6PD activity and also enhances 6PGL activity. We conclude that although the insertions are evolving rapidly they have an essential role in the activity of the bifunctional enzyme...

..CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS...

..These are the first natural mutations of TERT to be described and we highlight their possible pathogenic role in the development of bone marrow failure...

..The different characteristics of G6PD-6PGL with respect to its homologue in the host make it an ideal target for therapeutic strategies...

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