Down syndrome research
Research of Down syndrome-related genes is based on studying the genes located on chromosome 21. In general, this leads to an overexpression of the genes. Understanding the genes involved may help to target medical treatment to individuals with Down syndrome. It is estimated that chromosome 21 contains 200 to 250 genes. Recent research has identified a region of the chromosome that contains the main genes responsible for the pathogenesis of Down syndrome, located proximal to 21q22.3. The search for major genes involved in Down syndrome characteristics is normally in the region 21q21–21q22.3.
Genes
Some suspected genes involved in features of Down syndrome are given in the Table 1:| Gene | OMIM Reference | Location | Purported Function |
| APP | Amyloid precursor protein A4 precursor protein. Suspected to have a major role in cognitive difficulties. One of the first genes studied with transgenic mice with Down syndrome. | ||
| SOD1 | Superoxide dismutase. Possible role in Alzheimer's disease. Anti-oxidant as well as possible effects on the immuno-system. | ||
| DYRK | Dual-specificity Tyrosine Phosphorylation-Regulated Kinase 1A. May have an effect on mental development through abnormal neurogenesis. | ||
| IFNAR | Interferon, Alpha, Beta, and Omega, Receptor. Responsible for the expression of interferon, which affects the immuno-system. | ||
| DSCR1 | Down Syndrome Critical Region Gene 1. Possibly part of a signal transduction pathway involving both heart and brain. | ||
| COL6A1 | Collagen, type I, alpha 1 gene. May have an effect on heart disease. | ||
| ETS2 | Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have "demonstrated that overexpression of ETS2 results in apoptosis. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome." ETS2-Transgenic mice were also shown to "develop neurocranial, viscerocranial and cervical skeletal abnormalities", similar skeletal abnormalities to those seen in Down's Syndrome. | ||
| CRYA1 | Crystallin, Alpha-A. Involved in the synthesis of Crystallin, a major component of the lens in eyes. May be cause of cataracts. |
General research
Research by Arron et al. shows that some of the phenotypes associated with Down syndrome can be related to the disregulation of transcription factors, and in particular, NFAT. NFAT is controlled in part by two proteins, DSCR1 and DYRK1A; these genes are located on chromosome-21. In people with Down syndrome, these proteins have 1.5 times greater concentration than normal. The elevated levels of DSCR1 and DYRK1A keep NFAT primarily located in the cytoplasm rather than in the nucleus, preventing NFATc from activating the transcription of target genes and thus the production of certain proteins.This disregulation was discovered by testing in transgenic mice that had segments of their chromosomes duplicated to simulate a human chromosome-21 trisomy. A test involving grip strength showed that the genetically modified mice had a significantly weaker grip, much like the characteristically poor muscle tone of an individual with Down syndrome. The mice squeezed a probe with a paw and displayed a 0.2 newton weaker grip. Down syndrome is also characterized by increased socialization. When modified and unmodified mice were observed for social interaction, the modified mice showed as much as 25% more interactions as compared to the unmodified mice.
The genes that may be responsible for the phenotypes associated may be located proximal to 21q22.3. Testing by Olson and others in transgenic mice show the duplicated genes presumed to cause the phenotypes are not enough to cause the exact features. While the mice had sections of multiple genes duplicated to approximate a human chromosome-21 triplication, they only showed slight craniofacial abnormalities. The transgenic mice were compared to mice that had no gene duplication by measuring distances on various points on their skeletal structure and comparing them to the normal mice. The exact characteristics of Down syndrome were not observed, so more genes involved for Down syndrome phenotypes have to be located elsewhere.
Reeves et al., using 250 clones of chromosome-21 and specific gene markers, were able to map the gene in mutated bacteria. The testing had 99.7% coverage of the gene with 99.9995% accuracy due to multiple redundancies in the mapping techniques. In the study 225 genes were identified.
The search for major genes that may be involved in Down syndrome symptoms is normally in the region 21q21–21q22.3. However, studies by Reeves et al. show that 41% of the genes on chromosome-21 have no functional purpose, and only 54% of functional genes have a known protein sequence. Functionality of genes was determined by a computer using exon prediction analysis. Exon sequence was obtained by the same procedures of the chromosome-21 mapping.
Research has led to an understanding that two genes located on chromosome-21, that code for proteins that control gene regulators, DSCR1 and DYRK1A can be responsible for some of the phenotypes associated with Down syndrome. DSCR1 and DYRK1A cannot be blamed outright for the symptoms; there are a lot of genes that have no known purpose. Much more research would be needed to produce any appropriate or ethically acceptable treatment options.
Recent use of transgenic mice to study specific genes in the Down syndrome critical region has yielded some results. APP is an Amyloid beta A4 precursor protein. It is suspected to have a major role in cognitive difficulties. Another gene, ETS2 is Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have "demonstrated that over-expression of ETS2 results in apoptosis. Transgenic mice over-expressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome."