Single-minded 2 (Sim2), a transcriptional repressor, is reportedly involved in diseases that impair learning and memory, such as Down syndrome (DS) and Alzheimer's disease.
Here we studied functional genetic polymorphisms (fSNP) in ETS2 and SIM2 encoding genes in a group of patients and control subjects to better understand association of these variants with DS phenotypes.
These results suggest that MAD2B may mediate Sim2 function during development in CNS and thereby play a critical role in pathophysiological mechanisms in DS.
Significantly lower frequency of SIM2 C-G haplotype (rs2073601-rs2073416) was noticed in individuals with DS (P value =0.01669) and their fathers (P value=0.01185).
Drebrin has been reported to be engaged in dendritic-cytoskeleton modulation at synapses, and such a novel NXF signaling system on neural gene promoter may be a molecular target of the adverse effects of Sim2 in the mental retardation of Down's syndrome.
BACH1 was significantly overexpressed in fetal DS (p < 0.008) as compared to controls whereas RUNX1 and ERG proteins were comparable between groups, and SIM2 l was not detectable in any specimen.
There are no previous reports of this combination, but there are genetic links between Down syndrome and midline defects concerning the Drosophila single-minded (sim) gene.
However, three copies of SIM2 may contribute to some specific Down syndrome phenotypes because of (1) mapping position, (2) potential function as transcriptional repressor, (3) likely dimerization with other transcription factors, (4) the temporal and spatial expression pattern of mouse Sim2, and (5) the potentially analogous role of human SIM2 to that of Drosophila sim during neurogenesis.
During the course of an exon-trapping strategy aimed at identifying transcripts that contribute to the etiology and pathophysiology of Down syndrome, we identified a human exon from the Down syndrome critical region showing significant homology to the Drosophila sim gene.