DSCAM Gene
The second human DSCAM gene, DSCAML1, is located on chromosome band 11q23, a locus associated with Gilles de la Tourette and Jacobsen syndromes. However, the most intriguing changes in gene structure 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.
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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.
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