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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1246-1252.
Prepublished online as a Blood First Edition Paper on May 10, 2005; DOI 10.1182/blood-2005-01-0247.
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HEMATOPOIESIS
Identification and functional characterization of 2 variant alleles of the telomerase RNA template gene (TERC) in a patient with dyskeratosis congenita
Hinh Ly,
Mike Schertzer,
Wasil Jastaniah,
Jeff Davis,
Siu Li Yong,
Qin Ouyang,
Elizabeth H. Blackburn,
Tristram G. Parslow, and
Peter M. Lansdorp
From the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA; the Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; the Pediatric Hematology-Oncology Group, British Columbia's Children's Hospital, Vancouver, BC, Canada; the Department of Medical Genetics, Children & Women's Hospital Health Care Centre of BC, University of British Columbia, Vancouver, BC, Canada; the Department of Biochemistry and Biophysics, University of California, San Francisco, CA; and the Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
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.
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