Ly Hinh, Calado Rodrigo T, Allard Paulette, Baerlocher Gabriela M, Lansdorp Peter M, Young Neal S, Parslow Tristram G
Department of Pathology and Laboratory Medicine, Emory University, Whitehead Biomedical Research Bldg, 615 Michael St, Rm 175, Atlanta, GA 30322, USA.
Blood. 2005 Mar 15;105(6):2332-9. doi: 10.1182/blood-2004-09-3659. Epub 2004 Nov 18.
Human telomerase uses a specific cellular RNA, called hTERC, as the template to synthesize telomere repeats at chromosome ends. Approximately 10% to 15% of patients with aplastic anemia or other bone marrow failure syndromes are carriers of hTERC sequence variants whose functional significance, in most cases, is unknown. We screened 10 reported and 2 newly discovered hTERC variants from such patients and found that 10 of these negatively affected telomerase enzymatic function when they were used to reconstitute telomerase enzymatic function in human cells. Most functional deficits were due to perturbations of hTERC secondary structure and correlated well with the degrees of telomere shortening and reduced telomerase activity observed in peripheral blood lymphocytes of the representative patients. We also found no evidence of dominant-negative activity in any of the mutants. Therefore, loss of telomerase activity and of telomere maintenance resulting from inherited hTERC mutations may limit marrow stem cell renewal and predispose some patients to bone marrow failure.
人类端粒酶利用一种名为hTERC的特定细胞RNA作为模板，在染色体末端合成端粒重复序列。再生障碍性贫血或其他骨髓衰竭综合征患者中，约10%至15%是hTERC序列变异的携带者，在大多数情况下，其功能意义尚不清楚。我们从这些患者中筛选了10个已报道的和2个新发现的hTERC变异体，发现其中10个在用于在人类细胞中重建端粒酶酶功能时对端粒酶酶功能产生负面影响。大多数功能缺陷是由于hTERC二级结构的扰动，并且与在代表性患者外周血淋巴细胞中观察到的端粒缩短程度和端粒酶活性降低密切相关。我们还没有发现任何突变体存在显性负性活性的证据。因此，由遗传性hTERC突变导致的端粒酶活性丧失和端粒维持功能丧失可能会限制骨髓干细胞的更新，并使一些患者易患骨髓衰竭。
