Overexpression of C1-tetrahydrofolate synthase in fetal Down Syndrome brain

  • M. Fountoulakis
  • T. Gulesserian
  • G. Lubec
Part of the Journal of Neural Transmission Supplement 67 book series (NEURAL SUPPL, volume 67)


Trisomy 21, Down Syndrome, is the most common genetic cause of human mental retardation and results from non-disjunction of chromosome 21. Several reports have been linking folate metabolism to DS and indeed, chromosome 21 even encodes for a specific folate carrier. The availability of brain tissue along with the advent of proteomics enabled us to identify and quantify C1-tetrahydrofolate synthase (THF-S), a key element in folate metabolism in brain along with other enzymes involved in C1-metabolism.

Brains of controls and DS subjects at the 18th–19th week of gestation were homogenised and separated on 2 dimensional gel electrophoresis with subsequent in-gel digestion and mass spectrometrical identification and quantification with specific software.

THF-S was represented by three spots, possibly representing isoforms or posttranslational modifications. Two spots were significantly, about twofold, increased in fetal DS brain:

Controls [means ± SD: (spot 1) 2.55 ± 0.69; (spot 3) 1.39 ± 0.86] vs. Down syndrome [means ± SD: (spot 1) 4.25 ± 1.63; (spot 3) 4.43 ± 2.13].

These results were reproducible when THF-S levels were normalised versus the housekeeping protein actin and neuron specific enolase to compensate cell or neuronal loss.

C1-metabolism related enzymes ribose-phosphate pyrophosphokinase I, inositol monophosphate dehydrogenase, guanidine monophosphate synthease and S-adenosylmethionine synthase, gamma form, were comparable between groups.

Overexpression of this key enzyme in fetal DS brain at the early second trimester may indicate abnormal folate metabolism and may reflect folate deficiency. This may be of pathomechanistic relevance and thus extends and confirms the involvement of folate metabolism in trisomy 21.


Down Syndrome Neuron Specific Enolase Folate Metabolism Maternal Risk Factor Assisted Laser Desorption Ionisation Mass 
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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • M. Fountoulakis
    • 1
  • T. Gulesserian
    • 2
  • G. Lubec
    • 2
    • 3
  1. 1.Genomics and Proteomics TechnologiesHoffmann-La RocheBaselSwitzerland
  2. 2.Division Basic Research, Department of PediatricsUniversity of ViennaAustria
  3. 3.Department of PediatricsCChem, FRSC (UK), University of ViennaViennaAustria

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