TY - JOUR
T1 - Functional characterization of telomerase RNA variants found in patients with hematologic disorders
AU - Ly, Hinh
AU - Calado, Rodrigo T.
AU - Allard, Paulette
AU - Baerlocher, Gabriela M.
AU - Lansdorp, Peter M.
AU - Young, Neal S.
AU - Parslow, Tristram G.
PY - 2005/3/15
Y1 - 2005/3/15
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2004-09-3659
DO - 10.1182/blood-2004-09-3659
M3 - Article
C2 - 15550482
AN - SCOPUS:15244358401
SN - 0006-4971
VL - 105
SP - 2332
EP - 2339
JO - Blood
JF - Blood
IS - 6
ER -