Abstract
BackgroundLoss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation.MethodsBecause human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7).ResultsDepletion of LARP7 caused a reduction in telomerase enzymatic activity and progressively shorter telomeres in human cancer cell lines. Alazami syndrome patients from two separate cohorts exhibited very short lymphocyte telomeres. Further, wild-type offspring of LARP7 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT) mutant cohorts.ConclusionsTogether, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals.
Highlights
Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation
Together, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with La Autoantigen Related Protein 7 (LARP7) deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals
In contrast to what would be expected based on the observations that LARP7 deficiency in Tetrahymena leads to lower levels of Telomerase RNA component (TERC) Ribonucleic acid (RNA) and Human telomerase reverse transcriptase (TERT) protein [9, 12, 13], in human cells we show that LARP7 stable knockdown does not reduce total telomerase Messenger ribonucleic acid (mRNA) levels
Summary
Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation. In Tetrahymena, depletion of the LARP7 ortholog, p65, leads to lower levels of TERT protein as well as telomerase RNA (TERC) component abundance, in addition to its role in telomerase holoenzyme assembly [9, 12, 13]. Because of the many associations between the probably ortholog of LARP7 in Tetrahymena and telomerase, as well as the known telomerase-relevant function of the La-family protein LARP3, we decided to investigate how LARP7 impacts telomere maintenance in humans, both in tissue culture as well as in two independent cohorts of human LARP7 loss-of-function mutants
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