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 Blood, 15 August 2007, Vol. 110, No. 4, pp. 1141-1146.
Prepublished online as a Blood First Edition Paper on May 3, 2007; DOI 10.1182/blood-2007-03-080044.

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HEMATOPOIESIS

Mutations in the SBDS gene in acquired aplastic anemia

Rodrigo T. Calado1, Solomon A. Graf1,2, Keisha L. Wilkerson1, Sachiko Kajigaya1, Philip J. Ancliff3, Yigal Dror4, Stephen J. Chanock5, Peter M. Lansdorp6, and Neal S. Young1

1 Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; 2 Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD; 3 Camelia Botnar Laboratories, Great Ormond Street Hospital, London, United Kingdom; 4 Cell Biology Program, Research Institute, Hospital for Sick Children and the University of Toronto, ON, Canada; 5 Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; 6 Terry Fox Laboratory, BC Cancer Research Centre, and the Department of Medicine, University of British Columbia, Vancouver, BC, Canada

Shwachman-Diamond syndrome (SDS; OMIM 260400 [OMIM] ), an inherited bone marrow failure syndrome, is caused by mutations in both alleles of the SBDS gene, which encodes a protein of unknown function. Here we report heterozygosity for the 258 + 2 T>C SBDS gene mutation previously identified in SDS patients in 4 of 91 patients with apparently acquired aplastic anemia (AA) but not in 276 ethnically matched controls (Fisher exact test, P < .004). Affected patients were young and had a poor outcome; they had reduced SBDS expression but no evidence of the pancreatic exocrine failure or skeletal abnormalities typical of SDS. Length of telomeres in granulocytes of SBDS heterozygous patients was short for their age, and in SDS patients with both SBDS alleles affected further analyzed, granulocytes' telomeres were even shorter, correlating in length with SBDS expression. Higher heterogeneity in telomere length also was observed in SDS patients. Telomerase activity of SBDS-deficient patients' lymphocytes was comparable with controls, and no physical interaction between SBDS protein and telomerase complex components (TERT or TERC) was established. We propose that heterozygosity for the 258 + 2 T>C SBDS mutation predisposes to AA by accelerating telomere shortening of leukocytes via a telomerase-independent mechanism.


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