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.