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Title: Kinetic modeling of metabolic changes in Down Syndrome
P80
Klipp, Edda

klipp@molgen.mpg.de
Max-Planck Institute for Molecular Genetics, Ihnestr. 73, 13195 Berlin, Germany

Human trisomy 21 causes a complex disease, the Down syndrome. The causal chain of altered phenotype in Down syndrome including changes in metabolism, abnormalities in brain development, altered risk for leukemia and certain types of cancer, remains to be discovered. It is discussed that these effects are most probably due to a gene-dosage effect and/or the action of specific genes located on HSA 21 [1, 2]. Despite the presence of three copies of chromosome 21 measurements indicate that chromosome 21 genes are not always 1,5-fold overexpressed whereas also genes from other chromosomes are altered in their expression compared to normal [3]. This points to a complicated regulatory network.
Additionally, biological transmethylation reactions have attracted attention since they are important in a variety of processes such as methylation of DNA. These reactions utilize S-Adenosylmethionine (SAM) as methyl donor. The methylation of CpG-islands plays an important role in the epigenetic regulation of gene expression.
We propose a mathematical model for the methionine metabolism to analyze whether a change in the activity of cystathionine-b synthetase (CBS), superoxide dismutase (SOD1) or DNA (cytosine-5-)-methyltransferase 3 (DNMT3) which are encoded on chromosome 21 can be related to a change in the cellular methylation potential. The results indicate that an overexpression of SOD1 or CBS lead to an inhibition of the methylation and that an overexpression of DNMT3 leads to an undersupply of SAM. Both effects support experimental results about a potential hypomethylation of DNA in Down Syndrome [4].
[1] Kahlem P, Yaspo ML, Gene Funct. Dis, 5-6, 175-183 , 2000.
[2] Antonarakis SE, Curr. Op. Gen. Develop., 11, 241-246, 2001.
[3] Seidl R, Cairns N, Lubec G, J. Neural Transm., Suppl 61, 247-261, 2001.
[4] Pogribna M, Melnyk S et al., Am. J.Hum. Genet., 69, 88-97, 2001.