Submitted July 12, 2006
Accepted September 2, 2006
Functional characterization of natural telomerase mutations found in patients with hematological disorders
Zhong-Tao Xin, Adam D. Beauchamp, Rodrigo T. Calado, Jennifer W. Bradford, Joshua A. Regal, Aarthi Shenoy, Yuying Liang, Peter M. Lansdorp, Neal S. Young, and Hinh Ly*
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA
National Heart, Lung, and Blood Institute, Hematology Branch, Bethesda, MD
Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada
* Corresponding author; email: hly{at}emory.edu.
Human telomerase hTERC RNA serves as a template for the catalytic hTERT protein to synthesize telomere repeats at chromosome ends. We have recently shown that some patients with bone marrow failure syndromes are heterozygous carriers for hTERC or hTERT mutations. These sequence variations usually lead to a compromised telomerase function by haploinsufficiency. Here, we provide functional characterization of an additional 8 distinct hTERT sequence variants and 5 hTERC variants that have recently been identified in patients with dyskeratosis congenita (DC) or aplastic anemia (AA). Among the mutations, two are novel telomerase variants that were identified in our cohort of patients. While most of the sequence variants modulate telomerase function by haploinsufficiency, two hTERC variants with sequence changes located within the template region appeared to act in a dominant negative fashion. Inherited telomerase gene mutations, therefore, operate by various mechanisms to shorten telomere lengths, leading to limited marrow stem-cell reserve and renewal capacity in patients with hematologic disorders.
