Down syndrome (DS), caused by trisomy 21, is the most common birth defect associated with intellectual disability. DSCAM plays a crucial role in the development of DS: it is expressed in the developing nervous system, with the highest level of expression occurring in the fetal brain. When over-expressed in the developing fetal central nervous system, it leads to Down syndrome.
A homologue of the Dscam protein in Drosophila melanogaster has 38,016 isoforms arising from four variable exon clusters (12, 48, 33 and 2 alternatives, respectively).By comparison, the entire Drosophila melanogaster genome only has 15,016 genes. The diversity of isoforms from alternative splicing of the Dscam1 gene in D. melanogaster allows every neuron in the fly to display a unique set of Dscam proteins on its cell surface. Dscam interaction stimulates self-avoidance mechanisms that are essential for normal neural circuit development.
The DSCAM protein structure is conserved, with roughly more than 20% amino acid identity across the deuterostomes and protostomes, and assuming an ancestral homologous gene, places the origin of the DSCAM gene at >600 million years ago. Since then, the DSCAM gene has been duplicated at least once in vertebrates and insects.
DSCAM was first identified in an effort to characterize proteins located within human chromosome band 21q22, a region known to play a critical role in Down syndrome.[7] The name Down syndrome cell adhesion molecule was chosen for a combination of reasons including:
The DSCAM gene has been identified in the DS critical region. Dscam is predicted to be a transmembrane protein and a member of the immunoglobulin (Ig) superfamily of cell adhesion molecules. It is expressed in the developing nervous system with the highest level of expression occurring in the fetal brain. When this gene is over-expressed in the developing fetal central nervous system, it leads to Down syndrome. Diverse glycoproteins of cell surfaces and extracellular matrices, operationally termed as 'adhesion molecules' are important in the specification of cell interactions during development as well as maintenance and regeneration of the nervous system.
Another DSCAM-like gene, DSCAML1, is located on chromosome band 11q23, a locus associated with Gilles de la Tourette and Jacobsen syndromes.
Some intriguing changes in the gene structure of DSCAM have occurred in arthropods where several duplications of exons generated three large tandem arrays that are alternatively spliced.This alternative splicing of individual exon sequences within an array occurs in a mutually exclusive and combinatorial manner allowing for expression of tens of thousands of Dscam isoforms. In the arthropods' genomes these three large exon arrays encode the N-terminal halves of the second and third Ig domains and the full Ig7 domain.
Alternative splicing generates large number of isomers with different protein–protein interaction possibilities.
(i) DSCAM has 24 exons; exon 4 has 12 variants, exon 6 has 48 variants, exon 9 has 33 variants, and exon 17 has two variants. The combination of exons 4, 6, and 9 leads to 19,008 possible isoforms with different extracellular domains (due to differences in Ig2, Ig3 and Ig4). With two different transmembrane domains from exon 17, the total possible protein products could reach 38,016 isoforms.
(ii) These isoforms have different specific interactions due to structural variability.
(iii) For example, the crystal structures of two isoforms (first four domains only) revealed large variation in their binding epitopes, resulting in totally different dimer forms. Red ribbons represent the structure of isoform D9.9 which is the product of variant 9 of exon 4 and variant 9 of exon 6 (PDB code 2V5R), the green ribbons represents isoform D1.34, which is the product of variant 1 of exon 4 and variant 34 of exon 6 (PDB code 2V5S). The figure in the lower left corner is the superimposition of the two monomers of D9.9 and D1.34 with the differences in the large Ig3 domain loop highlighted. The figure in the lower right corner is the superimposition of two dimers of D9.9 and D1.34, with a completely different interface and dimer conformations.
Comparing the homology between genes and their products, is fundamental in understanding the phylogenetic relationship across the evolutionary pathway. In addition to the thousands of isoforms that can be populated from a single DSCAM of one species, DSCAM also demonstrates a diverse array of homology across species. Below are the genes, mRNA transcripts, and proteins identified as homologs of Down syndrome adhesion molecule.
Source: https://en.wikipedia.org/wiki/DSCAM
Image Source:
