|
|
Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-05-1537.
Submitted May 14, 2003
Accepted June 30, 2003
Defective RNA ribose synthesis in fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA)
Laszlo G Boros*, Mara P Steinkamp, Judith C Fleming, Wai-Nang Paul Lee, Marta Cascante, and Ellis J Neufeld
Department of Pediatrics, Harbor-UCLA Research & Education Institute, Torrance, CA, USA
Division of Hematology/Oncology, Department of Pediatrics, Childrens Hospital, Boston, MA, USA
Department of Pediatrics, Dana Farber Cancer Institute, Boston, MA, USA
Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
* Corresponding author; email: boros{at}gcrc.rei.edu.
Fibroblasts from patients with thiamine-responsive megaloblastic anemia syndrome with diabetes and deafness (TRMA) 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 (SIDMAP) technique to demonstrate that defective high-affinity thiamine transport primarily affects the synthesis of nucleic acid ribose via the non-oxidative 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 2-4 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 vs. control fibroblasts in the pentose and TCA cycles. We conclude that reduced nucleic acid production through impaired transketolase catalysis is the underlying biochemical disturbance which 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.
 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]
|
|
|
| |
