Impaired telomere maintenance in Alazami syndrome patients with LARP7 deficiency.

BACKGROUND: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. METHODS:Because human is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of Lduanyu377 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of of Lduanyu377 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 Lduanyu377 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT) mutant cohorts. CONCLUSIONS:Together, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with Lduanyu377 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals.

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