Aberrant Chromosome 21 Gene Products: Explaining the Down Syndrome Phenotype?
Neuroembryology and Aging
Although Down syndrome (DS; trisomy 21) has been known for more than a hundred years, mechanisms to explain the development of the DS phenotype are elusive. Also, sequencing of the entire human chromosome 21 did not lead to a breakthrough. A few candidate genes encoded on chromosome 21 have been proposed to play a pathogenetic role, but most studies were carried out in nonneural tissues and are therefore not useful for explaining the CNS phenotype and mental retardation, the cardinal symptom of
... cardinal symptom of DS besides dysmorphic features. The majority of studies on genetic changes in DS have been carried out at the RNA level, but there is a long and unpredictable pathway from RNA to the proteins that carry out functions, and systematic work on protein expression in the brain is missing. There are, however, several publications on individual protein derangements [1, 2], and we therefore decided to determine chromosome 21 gene products in fetal human DS brain. We used cortical tissue of fetal female controls (n = 6) and DS brain (n = 8) from the 18th-19th week of gestation (obtained from the Fetal Down Syndrome Brain Bank, Dr. M. Dierssen, Barcelona, Spain). This tissue was homogenized, then the protein concentration was determined and Western blotting was performed on samples as described previously  . The antibodies used were obtained from other scientists or purchased, and corre-sponding secondary antibodies were commercially available. Some proteins were determined by two-dimensional gel electrophoresis with subsequent mass spectrometric identification and quantification using specific software. Quantification of immunoreactivities showed that chromosome 21 gene products in fetal DS brain were comparable to those of controls for the vast majority of observations. A handful of proteins whose genes are encoded on chromosome 21 were aberrantly expressed. The human reduced folate carrier was overexpressed in DS, and this may be of relevance for abnormal development of the brain in DS, as deterioration of folate metabolism has already been reported in DS and has even been linked to nondisjunction and an increased risk of developing DS  . Chromosome assembly factor (CHAF-1 p60) was significantly increased in DS cortex as well, possibly indicating defective DNA repair due to oxidative DNA damage observed in DS. Increased synaptojanin levels in fetal DS brain confirmed previous observations that this protein is manifold (rather than the expected 150% by gene dosage) upregulated in DS, which may contribute to abnormal signaling in DS brain as this protein represents polyphosphoinositide phosphatase activity. Overexpression of DSCR5, a phosphatidyl-inositol-glycan class P protein, in turn points to the involvement of phosphoinositol cascades in DS.