TY - JOUR
T1 - Identification and functional characterization of 2 variant alleles of the telomerase RNA template gene (TERC) in a patient with dyskeratosis congenita
AU - Ly, Hinh
AU - Schertzer, Mike
AU - Jastaniah, Wasil
AU - Davis, Jeff
AU - Yong, Siu Li
AU - Ouyang, Qin
AU - Blackburn, Elizabeth H.
AU - Parslow, Tristram G.
AU - Lansdorp, Peter M.
PY - 2005/8/15
Y1 - 2005/8/15
N2 - Heterozygous mutations of the human telomerase RNA template gene (TERC) have been described in patients with acquired aplastic anemia and the autosomal dominant form of dyskeratosis congenita (DKC). Patients with mutations in both TERC alleles have not yet been reported. Here, we report a patient with DKC who inherited 2 distinct TERC sequence variants from her parents; a deletion (216_229del) in one and a point mutation (37A>G) in the other allele of the TERC gene, Her marrow was hypocellular and showed an abnormal clone [46, XX t(7; 21)(q34;q22)]. The telomere lengths in leukocytes of the patient and her relatives were shorter than those of the age-matched controls and were progressively shorter in subsequent generations of family members with the 216_229del allele. Telomerase enzymatic levels in lymphocytes from the patient were approximately half of those measured in healthy controls. The 216_229del mutation failed to reconstitute telomerase activity in transfected cells, but, when coexpressed with the 37A>G variant, telomerase activity was only modestly suppressed. These clinical and laboratory findings support the concept that telomerase levels in human hematopoietic stem cells are tightly controlled as even moderately reduced levels result in accelerated telomere shortening and eventual marrow failure.
AB - Heterozygous mutations of the human telomerase RNA template gene (TERC) have been described in patients with acquired aplastic anemia and the autosomal dominant form of dyskeratosis congenita (DKC). Patients with mutations in both TERC alleles have not yet been reported. Here, we report a patient with DKC who inherited 2 distinct TERC sequence variants from her parents; a deletion (216_229del) in one and a point mutation (37A>G) in the other allele of the TERC gene, Her marrow was hypocellular and showed an abnormal clone [46, XX t(7; 21)(q34;q22)]. The telomere lengths in leukocytes of the patient and her relatives were shorter than those of the age-matched controls and were progressively shorter in subsequent generations of family members with the 216_229del allele. Telomerase enzymatic levels in lymphocytes from the patient were approximately half of those measured in healthy controls. The 216_229del mutation failed to reconstitute telomerase activity in transfected cells, but, when coexpressed with the 37A>G variant, telomerase activity was only modestly suppressed. These clinical and laboratory findings support the concept that telomerase levels in human hematopoietic stem cells are tightly controlled as even moderately reduced levels result in accelerated telomere shortening and eventual marrow failure.
UR - http://www.scopus.com/inward/record.url?scp=23744511264&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=23744511264&partnerID=8YFLogxK
U2 - 10.1182/blood-2005-01-0247
DO - 10.1182/blood-2005-01-0247
M3 - Article
C2 - 15886322
AN - SCOPUS:23744511264
SN - 0006-4971
VL - 106
SP - 1246
EP - 1252
JO - Blood
JF - Blood
IS - 4
ER -