Authors: Zeng, Xi-Lei; Thumati, Naresh R.; Fleisig, Helen B.; Hukezalie, Kyle R.; Savage, Sharon A.; Giri, Neelam; Alter, Blanche P.; Wong, Judy M.Y.

Source: Human Molecular Genetics, Volume 21, Number 4, 15 February 2012 , pp. 721-729(9)

Publisher: Oxford University Press

Abstract:

X-linked dyskeratosis congenita (X-DC) is caused by mutations in the housekeeping nucleolar protein dyskerin. Amino acid changes associated with X-DC are remarkably heterogeneous. Peripheral mononuclear blood cells and fibroblasts isolated from X-DC patients harbor lower steady-state telomerase RNA (TER) levels and shorter telomeres than healthy age-matched controls. Previously, we showed that retroviral expression of recombinant TER, together with expression of recombinant telomerase reverse transcriptase, restored telomere maintenance and proliferative capacity in X-DC patient cells. Using rare X-DC isoforms (▵L37 and A386T dyskerin), we showed that telomere maintenance defects observed in X-DC are solely due to decreased steady-state levels of TER. Disease-associated reductions in steady-state TER levels cause deficiencies in telomere maintenance. Here, we confirm these findings in other primary X-DC patient cell lines coding for the most common (A353V dyskerin) and more clinically severe (K314R and A353V dyskerin) X-DC isoforms. Using cell lines derived from these patients, we also examined the steady-state levels of other hinge-ACA motif RNAs and did not find differences in their in vivo accumulations. We show, for the first time, that purified telomerase holoenzyme complexes from different X-DC cells have normal catalytic activity. Our data confirm that dyskerin promotes TER stability in vivo, endorsing the development of TER supplementation strategies for the treatment of X-DC.

Document Type: Research article

DOI: http://dx.doi.org/10.1093/hmg/ddr504

Publication date: 2012-02-15

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• Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics.

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• By this author: Zeng, Xi-Lei ;  Thumati, Naresh R. ;  Fleisig, Helen B. ;  Hukezalie, Kyle R. ;  Savage, Sharon A. ;  Giri, Neelam ;  Alter, Blanche P. ;  Wong, Judy M.Y.

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