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Blood, 15 January 2005, Vol. 105, No. 2, pp. 682-688.
Prepublished online as a Blood First Edition Paper on July 6, 2004; DOI 10.1182/blood-2004-04-1673.
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Submitted April 30, 2004
Accepted June 16, 2004
Association of Immune Abnormalities with Telomere Shortening in Autosomal Dominant Dyskeratosis Congenita
Matt Knudson, Shashikant Kulkarni, Zuhair Ballas, Monica Bessler, and Frederick Goldman*
Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Department of Internal Medicine, University of Iowa Hospitals and Clinics and Iowa City Veterans Affairs Medical Center, Iowa City, IA, USA
* Corresponding author; email: frederick-goldman{at}uiowa.edu.
Dyskeratosis congenita (DC) is an inherited bone marrow failure disorder characterized by abnormal skin pigmentation and nail dystrophy. We have recently described an autosomal dominant form of DC (AD DC) in ten members of a large 3 generation family that is due to a mutation in the gene encoding human telomerase RNA (TERC), resulting in telomere shortening. In studying the immunological consequences of TERC mutations, severe B lymphopenia and decreased IgM levels were noted. T cells were moderately decreased and overexpressed senescent markers, including CD57 and the Fas receptor. To determine whether these in vivo findings were related to cellular replicative defects, short-term cultures of AD DC lymphocytes were established to measure proliferation, mitoses, and apoptosis. AD DC lymphocytes displayed a markedly reduced proliferative capacity and increased basal apoptotic rate. Finally, telomere shortening was most prominent and progressive in 3rd generation subjects, and there appeared to be a correlation between telomere length and in vivo and in vitro immune findings. In summary, the observed lymphopenia and hypogammaglobulinemia in AD DC is likely a consequence of replicative failure and premature senescence of lymphocytes, supporting a role of telomerase activity in immune homeostasis.
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