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Blood, 15 November 2003, Vol. 102, No. 10, pp. 3556-3561. Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-05-1537. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-05-1537v1 102/10/3556    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Boros, L. G. Articles by Neufeld, E. J. Search for Related Content PubMed PubMed Citation Articles by Boros, L. G. Articles by Neufeld, E. J. Related Collections Apoptosis Cell Cycle Signal Transduction Hematopoiesis Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Defective RNA ribose synthesis in fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA) László G. Boros, Mara P. Steinkamp, Judith C. Fleming, Wai-Nang Paul Lee, Marta Cascante, and Ellis J. Neufeld From the Harbor-University of California, Los Angeles (UCLA) Research and Education Institute, UCLA School of Medicine, Torrance, CA; the Division of Hematology/Oncology, Children's Hospital, Boston, MA; the Dana Farber Cancer Institute and Harvard Medical School, Boston, MA; and the Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Catalonia, Spain. Fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA) syndrome with diabetes and deafness undergo apoptotic cell death in the absence of supplemental thiamine in their cultures. The basis of megaloblastosis in these patients has not been determined. Here we use the stable [1,2-13C2]glucose isotope-based dynamic metabolic profiling technique to demonstrate that defective high-affinity thiamine transport primarily affects the synthesis of nucleic acid ribose via the nonoxidative branch of the pentose cycle. RNA ribose isolated from TRMA fibroblasts in thiamine-depleted cultures shows a time-dependent decrease in the fraction of ribose derived via transketolase, a thiamine-dependent enzyme in the pentose cycle. The fractional rate of de novo ribose synthesis from glucose is decreased several fold 2 to 4 days after removal of thiamine from the culture medium. No such metabolic changes are observed in wild-type fibroblasts or in TRMA mutant cells in thiamine-containing medium. Fluxes through glycolysis are similar in TRMA versus control fibroblasts in the pentose and TCA cycles. We conclude that reduced nucleic acid production through impaired transketolase catalysis is the underlying biochemical disturbance that likely induces cell cycle arrest or apoptosis in bone marrow cells and leads to the TRMA syndrome in patients with defective high-affinity thiamine transport. (Blood. 2003;102: 3556-3561) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W.-N. P. Lee and V. L. W. Go Nutrient-Gene Interaction: Tracer-Based Metabolomics J. Nutr., December 1, 2005; 135(12): 3027S - 3032S. [Abstract] [Full Text] [PDF] M E Baser, V-F Mautner, D M Parry, and D G R Evans Methodological issues in longitudinal studies: vestibular schwannoma growth rates in neurofibromatosis 2 J. Med. Genet., December 1, 2005; 42(12): 903 - 906. [Abstract] [Full Text] [PDF] J R Porter and T G Barrett Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and {beta} cell failure J. Med. Genet., December 1, 2005; 42(12): 893 - 902. [Abstract] [Full Text] [PDF] I. Sahai, M. C. Montefusco, J. C. Fleming, L. Boros, E. Tartaglini, G. Chick, and E. J. Neufeld Role of Defective High-Affinity Thiamine Transporter slc19a2 in Marrow from a Mouse Model of Thiamine-Responsive Anemia Syndrome: Evidence for Defective Deoxyribose and Heme Synthesis. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 516 - 516. [Abstract]

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